Download Membrane-shaping disorders: a common pathway in axon

doi:10.1093/brain/awu287
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BRAIN
A JOURNAL OF NEUROLOGY
REVIEW ARTICLE
Membrane-shaping disorders: a common pathway
in axon degeneration
Christian A. Hübner and Ingo Kurth
Institute of Human Genetics, Jena University Hospital, 07743 Jena, Germany
Correspondence to: Ingo Kurth
E-mail: [email protected]
Correspondence may also be addressed to: Christian A. Hübner
E-mail: [email protected]
Neurons with long projections are particularly liable to damage, which is reflected by a large group of hereditary neurodegenerative
disorders that primarily affect these neurons. In the group of hereditary spastic paraplegias motor axons of the central nervous
system degenerate, while distal pure motor neuropathies, Charcot-Marie-Tooth disorders and the group of hereditary sensory and
autonomic neuropathies are characterized by degeneration of peripheral nerve fibres. Because the underlying pathologies share
many parallels, the disorders are also referred to as axonopathies. A large number of genes has been associated with axonopathies
and one of the emerging subgroups encodes membrane-shaping proteins with a central reticulon homology domain. Association of
these proteins with lipid bilayers induces positive membrane curvature and influences the architecture of cellular organelles.
Membrane-shaping proteins closely cooperate and directly interact with each other, but their structural features and localization
to distinct subdomains of organelles suggests mutually exclusive roles. In some individuals a mutation in a shaping protein can
result in upper motor neuron dysfunction, whereas in other patients it can lead to a degeneration of peripheral neurons. This
suggests that membrane-shaping disorders might be considered as a continuous disease-spectrum of the axon.
Keywords: HSAN; HSP; axonopathies; reticulon; membrane-shaping; neurodegeneration, pain
Abbreviations: HSAN = hereditary sensory and autonomic neuropathy; HSP = hereditary spastic paraplegia
Introduction
Neurons of both efferent and afferent pathways are characterized by
exceptionally long projections. Cortical motor neurons project to
spinal cord motor neurons that subsequently innervate the skeletal
muscle. Together both neurons bridge a distance of 1.5 m. A similar
neuronal circuit is present in sensory afferent fibre tracts that mediate
touch, vibration, warmth, cold, itch or pain (Fig. 1). The extraordinary
length of these axons requires highly efficient mechanisms of cellular
communication and signalling that may also explain why these structures are particularly susceptible to damage. A loss of long projections
that connect upper cortical neurons with -motor neurons results in a
spastic gait disorder as hallmark of the large group of hereditary
spastic paraplegias (HSPs), whereas a degeneration of peripheral
motor neurons causes muscle weakness in distal pure motor neuropathy (HMN) or Charcot-Marie-Tooth neuropathy type 2 (CMT2).
Predominant degeneration of afferent fibres is typical for hereditary
sensory and autonomic neuropathies (HSAN) and results in a sensory
loss that ranges from local numbness to a complete inability to experience pain. Affected individuals are at permanent risk for injuries.
Delayed wound healing, osteomyelitis, and neuropathic arthropathy
can further complicate the disease (Rotthier et al., 2012; AuerGrumbach, 2014). The concurrent involvement of autonomic fibre
tracts in some individuals leads to hyperhidrosis, tonic pupils, urinary
incontinence, gastrointestinal dysfunction, or cardiovascular instability.
Despite their different clinical symptoms these neurodegenerative disorders are summarized as length-dependent axonopathies
and constitute one of the most common groups of hereditary
Received June 27, 2014. Revised August 14, 2014. Accepted August 19, 2014. Advance Access publication October 4, 2014
ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
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C. A. Hübner and I. Kurth
Figure 1 Long fibre tracts in the human body. Efferent axons project from the motor cortex to lower motor neurons in the ventral column
of the spinal cord and innervate voluntary muscles. Vice versa, pseudounipolar afferent neurons mediate sensory perception (temperature,
touch, pain) by projecting to higher order neurons in the dorsal laminae of the spinal cord. The signal is further processed in thalamic nuclei
and the somatosensory cortex. Membrane-shaping proteins implicated in the degeneration of long fibre tracts are displayed at their main
site of clinical manifestation.
disorders. Causative genes play a role in different cellular processes
including axonal transport, lipid metabolism, neurotrophin signalling, or endosomal trafficking. However, there is growing evidence
that a class of membrane-shaping proteins is of particular importance for the long-term survival of axons.
Membrane curvature
generation
Membranes are flexible barriers that surround the cell and its compartments. To enable vital functions such as cell migration, cell division, endocytosis, and secretion, cells need to control the shape of
their membranes with high spatial and temporal accuracy.
Intracellular membranes constantly undergo dynamic remodelling
processes as exemplified by fusion and fission events. Soluble Nethylmaleimide-sensitive factor activating protein receptor (SNARE)
and Sec1/Munc18-like (SM) proteins play a crucial and complementary role in membrane dynamics by fusing transport vesicles with
their target membranes (Südhof and Rothman, 2009). On the
other hand, membrane fission events are mediated by dynamin proteins wrapping a helix around a tubule and constricting it by hydrolysis of GTP (Praefcke and McMahon, 2004). Another example is the
permanent exchange between endoplasmic reticulum and Golgi
apparatus, which involves a bidirectional cargo selection and delivery
machinery that recruits the cytosolic coat protein complexes COPI
and COPII to deform flat membranes into round buds (Barlowe
et al., 1994; Bonifacino and Glick, 2004; Lee et al., 2004).
However, despite constant membrane remodelling cellular organelles maintain a characteristic shape. In the case of the Golgi
apparatus the typical morphology is established by a stacking of
several membranes, while mitochondria adopt a rod-shaped structure with an outer and an inner membrane. The endoplasmic reticulum provides an example of the extraordinary structural
complexity of organelles and is composed of the nuclear envelope
and a continuous cellular network of sheets and tubules.
The shape of organelles results from the elastic properties and
curvature energy of a system of closed lipid bilayers and depends
on the particular lipid composition of each leaflet of the membrane
(Helfrich, 1973; Zimmerberg and Kozlov, 2006). In addition, integral membrane proteins and associated proteins establish higher
curvature of lipid bilayers by different mechanisms. Curved protein
scaffolds e.g. attach to membranes and force the bilayer to adopt
the rigid shape of the scaffold. Moreover, motor proteins produce
mechanical force by attaching to membranes and pulling them
along the cytoskeleton (Shibata et al., 2009). A third mechanism
is the insertion of a wedge-shaped hydrophobic surface into the
membrane as exemplified by a class of reticulon-domain
Membrane-shaping disorders
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Figure 2 A hydrophobic reticulon-domain (indicated in light pink) is a feature of different proteins involved in the function of sensory and
motor neurons. Reticulon-domain containing proteins contribute to the architecture of organelle membranes by adopting a hairpin
insertion into the lipid bilayer. This topology may create positive membrane curvature because the bulk of hydrophobic residues occupies
space in the outer leaflet of the lipid bilayer. The insert shows membrane-shaping proteins implicated in axon degeneration and respective
human disorders are indicated in brackets. A prototype reticulon domain is a common feature of reticulon 2 (RTN2), FAM134B, and
ARL6IP1 (light pink). Membrane-shaping properties by hairpin loop insertion were also proposed for REEP1, REEP2, spastin, and proteins
of the atlastin family, ATL1 and ATL3 (respective domains are given in dark pink). Of note, alternative models for the membrane insertion
have been proposed for some of the proteins. CC = coiled-coil domain; MTB = microtubule binding domain; MIT = microtubule interacting and trafficking molecule domain; AAA = ATPase domain associated with various activities; GTB = GTP-binding domain;
ER = endoplasmic reticulum.
containing proteins. This latter group of proteins are a major determinant to achieve high membrane curvature and seem to be of
particular importance for neuronal homeostasis.
The reticulon-domain: driving
force in bending lipid bilayers
Four genes encoding reticulon proteins have been identified in
mammals: RTN1, RTN2, RTN3, and RTN4/NOGO (Wieczorek
and Hughes, 1991; Oertle et al., 2003; Di Sano et al., 2012).
Reticulons are defined by an evolutionarily conserved C-terminal
‘reticulon homology domain’ characterized by two unusually long
hydrophobic regions that are interrupted by a hydrophilic loop
(Yang and Strittmatter, 2007). The length of each of the
hydrophobic segments exceeds the average length (20–25 amino
acids) of an alpha-helical domain passing the lipid bilayer, although a dichotomy in transmembrane domain length between
the early and late parts of the secretory pathway has been reported (Sharpe et al., 2010). It was elegantly demonstrated that
the hydrophobic stretches of the reticulon domain insert into lipid
bilayers as a hairpin, presumably without entirely passing the
membrane (Voeltz et al., 2006) (Fig. 2). It is assumed that this
unusual hairpin topology occupies more space on the outer leaflet
of the lipid bilayer than on the inner leaflet and produces positive
membrane curvature which allows the formation of membrane
tubules (Hu et al., 2008). Reticulon proteins are enriched in
membranes of the endoplasmic reticulum where they contribute
to the shape of the endoplasmic reticulum network.
Overexpression of reticulons generates long unbranched tubules,
whereas depletion leads to loss of the tubular endoplasmic
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reticulum (Voeltz et al., 2006). Reticulon proteins also form complexes that might cooperate in bending organelle membranes
(Borgese et al., 2006; Shibata et al., 2008).
Structurally related hairpin-domains were postulated for
FAM134 proteins, ARL6IP1, REEPs, spastin/SPAST, and atlastin
molecules (Fig. 2). In this review we will give an update about
the different membrane-shaping proteins involved in axonopathies
and summarize current knowledge on their function.
Mutations in membraneshaping proteins and axon
degeneration
In the following the different proteins implicated in membraneshaping disorders will be discussed. Table 1 summarizes the
main clinical findings.
ARL6IP1
ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) was
named after its interaction with ARL6 and was initially characterized as an endoplasmic reticulum-resident anti-apoptotic regulator
(ARMER) (Lui et al., 2003). The protein also modulates neural
glutamate transport (Akiduki and Ikemoto, 2008) and is required
for neural crest and ocular development in zebrafish (Huang et al.,
2012; Tu et al., 2012).
Recently, a homozygous loss-of-function mutation in ARL6IP1
was identified in autosomal-recessive HSP (SPG61) by whole
exome-sequencing (Novarino et al., 2014). The study included
four affected members in different branches of a consanguineous
pedigree. Individuals presented with a complicated form of spastic
paraplegia with distal peripheral neuropathy beginning in infancy.
As loss of finger tips and acromutilations were reported, this
might indicate clinical overlap with sensory and autonomic neuropathies. Functional evidence for a role for Arl6ip1 in both touchinduced and spontaneous locomotion behaviour was provided
by morpholino experiments in zebrafish (Novarino et al., 2014).
Heterologously expressed ARL6IP1 shows a marked influence on
endoplasmic reticulum architecture in a reticulon-domain dependent manner (Yamamoto et al., 2014 and own observations),
which suggests that loss of ARL6IP1 may interfere with endoplasmic reticulum network maintenance. The reticulon-domain of
ARL6IP1 shows structural similarity to classical reticulon proteins.
However, an alternative topology was recently proposed
where the first of the two long hydrophobic stretches of
ARL6IP1 inserts into the membrane as hairpin whereas the
second hydrophobic stretch entirely crosses the membrane
(Kuroda et al., 2014).
ATL1
The atlastin family of dynamin-related GTPases encompasses three
proteins in humans (ATL1, ATL2, ATL3) (Rismanchi et al., 2008).
Altlastins contain a hairpin-domain and catalyse membrane fusion
and branching of endoplasmic reticulum tubules to generate the
C. A. Hübner and I. Kurth
network structure of the compartment (Hu et al., 2009; Muriel
et al., 2009; Orso et al., 2009). Upon GTP binding the cytosolic
GTPase domains of ATLs dimerize. The subsequent GTP hydrolysis
causes a major conformational change that pulls ATLs in opposing
membranes together to achieve membrane fusion (Bian et al.,
2011; Byrnes and Sondermann, 2011; Moss et al., 2011; Pendin
et al., 2011; Liu et al., 2012). ATLs have also been implicated in
the morphogenesis of the Golgi apparatus (Rismanchi et al., 2008)
and together with REEPs (receptor expression enhancing proteins)
regulate lipid droplet size (Klemm et al., 2013; Falk et al., 2014).
Lipid droplets act as intracellular lipid stores that reuse triacylglycerols to support energy supply, but are also involved in detoxification of excessive lipids (Farese and Walther, 2009). Atlastins
seem to be dispensable for the initial steps of lipid droplet formation, but mediate lipid droplet expansion in concert with REEP
proteins (Klemm et al., 2013).
Mutations in ATL1 (SPG3A) account for 10% of autosomaldominant pure/uncomplicated forms of HSP with an average age
of onset in early childhood. The disorder is characterized by spasticity, diminished vibration sense, and urinary bladder disturbances
(Durr et al., 2004). Penetrance is high but may be incomplete.
Complicated forms of HSP with axonal motor neuropathy and
distal amyotrophy have been observed and are referred to as
‘Silver syndrome phenotype’. Recently, evidence was provided
that specific ATL1 missense mutations may result in autosomalrecessive HSP (Khan et al., 2014). Interestingly, heterozygous mutations in ATL1 can also cause autosomal-dominant sensory neuropathy (HSAN1) (Guelly et al., 2011). First symptoms in the
ATL1-associated sensory neuropathy arise in early adulthood
with severe distal sensory loss and distal amyotrophy. Trophic
skin and nail changes and repeated foot ulcerations leading to
osteomyelitis and subsequent foot or toe amputations are typical.
Some patients show upper motor neuron involvement in line with
the SPG3A phenotype (Guelly et al., 2011).
ATL3
ATL3 shows predominant localization to the endoplasmic reticulum and is enriched in endoplasmic reticulum branching points,
termed ‘three-way junctions’ (English and Voeltz, 2013b; Kornak
et al., 2014). Missense-mutations in ATL3 were recently identified
in multi-generation families with autosomal-dominant sensory
neuropathy (HSAN1) (Fischer et al., 2014; Kornak et al., 2014).
The ATL3 disorder is characterized by adult-onset painless chronic
ulcerations and fractures of the metatarsals, which may result in
severe bone destruction. Wound healing is typically delayed.
Motor nerve conduction velocities are in the normal range,
whereas sensory nerve conduction studies reveal signs of an
axonal sensory neuropathy. Remarkably, mutations of the homologous amino acid residues are known for ATL1, where they
cause a spastic paraplegia phenotype (McCorquodale et al.,
2011; de Bot et al., 2013). Functional studies indicated that the
cellular endoplasmic reticulum network is disrupted upon heterologous expression of mutant ATL3 proteins, indicating that
HSAN1-associated mutations produce a dominant-negative effect
(Kornak et al., 2014). This is further supported by the notion that
genomic copy number variants involving the ATL3 locus have not
SPG12
AD
AD
AR
AD
AD
AD and AR
AD
AD
Guelly et al., 2011
Kornak et al., 2014
Kurth et al., 2009
Zuchner et al., 2006
Beetz et al., 2012
Esteves et al., 2014;
Novarino et al., 2014
Montenegro et al., 2012
Hazan et al., 1999
ATL1
ATL3
FAM134B
REEP1
REEP1
REEP2
SPAST
SPG4A
HMN5B
SPG31
HSAN2B
HSN1F
HSN1D
SPG3A
182601
604805
615625
614751
610250
613115
615632
613708
182600
615685
OMIM
Complicated HSP with spasticity and distal peripheral neuropathy. No cerebellar
signs. No amyotrophy. Sensory loss. Loss of terminal digits and acropathy.
Sphincter disturbances not reported. Normal cognition. EMG/NCV: diffuse
motor and sensory polyneuropathy predominantly affecting lower limbs.
In most cases uncomplicated form of HSP, spastic gait. Lower limb spasticity and
weakness. Highly variable severity, reduced penetrance. Pes cavus, scoliosis.
Decreased vibratory sense in lower limbs. Sphincter disturbances. Complicated
forms with axonal motor neuropathy / distal amyotrophy with lower motor
neuron involvement are reported (Silver syndrome phenotype).
Distal sensory loss of all modalities (pain, temperature, touch, vibration). Distal
painless ulcers, trophic skin changes, dystrophic nails, necrosis and osteomyelitis, auto-amputations. Lower limbs are more affected than upper limbs.
Paraesthesia. Upper motor involvement and hyperreflexia in some patients. No
cognitive impairment. EMG/NCV: sensorimotor axonal neuropathy.
Distal sensory loss of all modalities (pain, temperature, touch, vibration). Distal
painless ulcers, trophic skin changes, dystrophic nails, necrosis and osteomyelitis, auto-amputations. Lower limbs are more affected than upper limbs. Slow
wound healing. Severe bone destruction. EMG/NCV: signs of sensory axonal
neuropathy.
Distal sensory loss, lower limbs more severly affected than upper limbs.
Unnoticed injuries, trophic skin changes, ulcerations, fractures, acroosteolysis,
auto-amputations. Autonomic disturbances include hyperhidrosis, tonic pupils,
urinary incontinence. No cognitive impairment. Upper motor neuron involvement in some cases: brisk reflexes, Babinski signs, spastic gait. EMG/NCV: signs
of sensory axonal neuropathy.
Uncomplicated form of HSP in most cases, spastic gait. Difficulty with balance,
muscle spasms. Complicated forms are reported. Muscle weakness, amyotrophy, ancle clonus. Less common: urinary urgency, dysphagia, distal sensory
loss.
Amyotrophy of the intrinsic hand muscles. Pes cavus, distal muscle weakness,
distal muscle atrophy. Hypo- or areflexia. Atrophy of small hand muscles. No
pyramidal tract features. EMG/NCV: decreased motor nerve conduction
amplitudes and velocities.
Uncomplicated form of HSP, spastic gait, muscle stiffness. Pes cavus. No cerebellar signs. Decreased vibration sense, sphincter disturbances.
Uncomplicated form of HSP, lower limb spasticity and weakness, hyperreflexia,
ankle or knee clonus, pes cavus. Decreased vibratory sense in the lower limbs.
Sphincter disturbances, urinary incontinence.
Uncomplicated form of HSP, spastic gait. Most common form of AD-HSP (40%
of the cases). Lower limb spasticity and weakness. Decreased vibratory sense in
the lower limbs, sphincter disturbances. Incomplete penetrance.
Clinical symptoms
Variable
1st–2nd decade, later
onset reported
Childhood
2nd decade
Variable, but mostly
before 3rd decade
1st-2nd decade
Adult onset
Adult onset
Usually
early childhood
Infancy
Age at onset
‘Uncomplicated’ forms of HSP are characterized by lower extremity spasticity and weakness. ‘Complicated’ forms are associated with additional symptoms, e.g. neuropathy, distal wasting, cerebellar symptoms, or intellectual
disability.
AD = autosomal dominant, AR = autosomal recessive; NCV = nerve conduction velocity.
RTN2
SPG72
AD (AR)
Zhao et al., 2001
ATL1
SPG61
AR
Novarino et al., 2014
ARL6IP1
Disorder
Inheritance
Reference
Gene
Table 1 Clinical features of membrane-shaping disorders
Membrane-shaping disorders
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been reported to be associated with a neuropathy phenotype (e.g.
Database of Genomic Variants, DGV).
FAM134B
FAM134B belongs to a family of three members with sequence
similarity (family with sequence similarity 134; FAM134A, -B, and
–C) that share a reticulon domain. FAM134B overexpression was
found in oesophageal squamous cell carcinomas and recently a
role in colorectal cancer was proposed (Tang et al., 2007;
Kasem et al., 2014). Moreover, FAM134B was reported as a
marker for pluripotent stem cells and as a susceptibility locus to
vascular dementia (Kong et al., 2011; Scheubert et al., 2011).
Homozygous germline loss-of-function mutations in FAM134B
result in hereditary sensory and autonomic neuropathy type 2
(HSAN2) (Kurth et al., 2009). The mutation spectrum of nonsense,
frameshift, and canonical splice-site mutations suggests a loss of
function mechanism (Kurth et al., 2009; Davidson et al., 2012;
Murphy et al., 2012; Aydinlar et al., 2014). Clinical hallmark is a
progressively reduced sensation to pain, temperature, and touch.
First symptoms can start at birth and occur before puberty. The
sensory deficit is predominantly distal with the lower limbs being
more severely affected than the upper limbs. Over time sensory
function becomes severely reduced. Unnoticed injuries and trophic
skin changes promote ulcerations and infections that result in
spontaneous amputation of digits or the need for surgical amputation (Fig. 3). Osteomyelitis is common and painless fractures can
complicate the disease. The autonomic disturbances are variable
and include hyperhidrosis, tonic pupils, and urinary incontinence in
those with more advanced disease (Kurth et al., 2009; Davidson
et al., 2012; Murphy et al., 2012). Affected individuals have no
cognitive impairment. However, it seems that CNS neurons can be
mildly involved, as a tetrapyramidal syndrome with brisk reflexes,
Babinski signs, and spastic gait has been reported (Kurth et al.,
2009). Early-onset walking difficulties with a proximal and distal
weakness in the lower extremities as well as spastic gait were also
reported (Aydinlar et al., 2014).
FAM134B predominantly localizes to the cis-Golgi apparatus of sensory and autonomic ganglia neurons and its
knockdown causes structural alterations of the Golgi apparatus
in neuronal cells (Kurth et al., 2009). In contrast, heterologous
overexpression of FAM134B results in predominant association
of the protein with the endoplasmic reticulum, where it induces
changes of the endoplasmic reticulum architecture (own unpublished data).
The role of FAM134A and FAM134C is less clear. While
FAM134A was found as a candidate for schizophrenia susceptibility (Shibata et al., 2013), a role of FAM134C in neurite outgrowth
was proposed (Wang et al., 2013).
REEP1
Receptor expression enhancing proteins (REEPs) were initially identified by their ability to enhance cell surface expression of distinct
G protein-coupled odorant receptors (Saito et al., 2004). All six
proteins of the human REEP family (REEP1–6) comprise a hairpin-domain, whereas only REEP1–4 interact with microtubules by
Figure 3 Mutilating sensory neuropathy type 2 (HSAN2) in an
individual with homozygous loss-of-function mutations in
FAM134B.
a cytoplasmic microtubule binding domain (Renvoise and
Blackstone, 2010). REEP1 was shown to function in a complex
with other hairpin-domain proteins including spastin and atlastins
to coordinate endoplasmic reticulum network formation and alignment along the microtubule cytoskeleton (Evans et al., 2006;
Sanderson et al., 2006; Park et al., 2010; Park and Blackstone,
2010). Additional roles such as enhancing endoplasmic reticulum
cargo capacity, regulating endoplasmic reticulum-Golgi processing,
or regulating lipid droplet size were reported (Bjork et al., 2013;
Klemm et al., 2013). Mutations in REEP1 cause autosomal-dominant HSP (SPG31) characterized by a progressive weakness and
spasticity of lower limbs (Zuchner et al., 2006). Early and late
onset disorders are described. Initial symptoms include difficulty
with balance, weakness, stiffness in the legs, and muscle spasms
(Beetz et al., 2008). However, the rate of progression and severity
of symptoms are highly variable. Most SPG31 patients present
with a pure spastic paraplegia, but in rare cases peripheral
nerves are involved. In some forms, bladder disturbances such as
urinary incontinence may appear and spasticity may affect other
parts of the body (Goizet et al., 2013). A yet unanswered question
is whether procedural learning deficits may also apply to REEP1
and HSP patients in general as motor cortex neurons not only
project to the spinal cord but also give off-collaterals that innervate the striatum (Deutch et al., 2013).
Membrane-shaping disorders
REEP1 is predominantly expressed in neurons and shows a particularly strong expression in cell bodies of upper motor neurons in
cortical layer V, consistent with the main pathology in HSP. REEP1
knockout mice display a progressive gait disorder closely resembling HSP in humans which confirms a loss-of-function mechanism
in SPG31 (Beetz et al., 2013b). Heterozygous knockout mice show
a loss of corticospinal tract axons, while the somata of cortical
neurons are largely preserved. In vitro reconstitution assays demonstrate that REEP1 directly associates with lipid bilayers and promotes positive membrane curvature, causing the constriction and
fission of liposomes (Beetz et al., 2013b) (Fig. 4). Supporting its
role in organelle architecture, heterozygous and even more pronounced homozygous REEP1 knockout mice show a reduced
number of endoplasmic reticulum structures in sections of CNS
neurons, whereas the length of individual endoplasmic reticulum
compartments was increased. This provides in vivo evidence for
a role of REEP1 in shaping the neuronal endoplasmic reticulum
(Fig. 4).
REEP2
REEP2 encodes the second member of the REEP family. REEP2
was shown to recruit sweet receptors into lipid raft microdomains
localized near the apical region of taste cells, thereby promoting
receptor access to tastants (Ilegems et al., 2010).
A heterozygous REEP2 missense variant was recently shown to
segregate in a large autosomal-dominant family with childhoodonset uncomplicated HSP (SPG72) (Esteves et al., 2014). Affected
individuals neither developed cerebellar symptoms nor mental impairment. Ambulation was preserved up to 60 years after onset of
symptoms, but severity was reported as variable within the family.
Functional studies suggested a dominant-negative effect of the
mutated REEP2 gene product by inhibiting the binding of wildtype REEP2 to membranes. In fibroblasts from an affected individual the protein abundance of REEP2 was not reduced, but the
endoplasmic reticulum sheets in fibroblasts were either irregularly
narrowed or expanded and swollen. Moreover, CLIMP-63, a luminal spacer of the rough endoplasmic reticulum, was distributed
more widely to the periphery of the cells (Esteves et al., 2014).
Interestingly, mutations in REEP2 can also cause autosomal-recessively inherited HSP with a similar clinical presentation (Esteves
et al., 2014). Autosomal-recessive inheritance was also shown in a
family with early-onset HSP, which carries a mutation of the canonical start codon (p.Met1Thr) of REEP2 (Novarino et al., 2014).
The findings exemplify that different modes of inheritance can be
caused by mutations in the same gene. Accordingly, careful interpretation of REEP2 testing results is necessary.
REEP2 harbours a long hydrophobic segment in line with a hairpin topology. However, alternative models have been proposed.
For example, it was suggested that the C-terminal hydrophobic
segment does not form a hairpin-loop but rather entirely crosses
the lipid bilayer (Ilegems et al., 2010). In this model REEP2 may
influence membrane bending in synergy with binding partners
such as other hairpin-domain containing proteins. Alternatively,
the long hydrophobic segment of REEP2 might adopt an uncommon spatial conformation that facilitates positive membrane
curvature.
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RTN2
The RTN2 gene encodes different isoforms of RTN2 (reticulon 2)
proteins that all have in common a C-terminally located prototype
reticulon-domain. Mutations in RTN2 cause autosomal-dominant
pure HSP, previously assigned to the SPG12 locus (Reid et al.,
2000; Orlacchio et al., 2002; Montenegro et al., 2012). The mutation spectrum suggests haploinsufficiency as the main pathomechanism of the disease. Onset of symptoms is variable between 5
and 40 years of age and includes lower limb spasticity and hyperreflexia, resulting in walking difficulties. Urinary symptoms and
distal sensory impairment have been reported for some patients.
The RTN2B isoform, which appears to be preferentially expressed
in brain, was shown to co-localize with endoplasmic reticulum
markers (Yang and Strittmatter, 2007). RTN2B interacts with
the reticulon-domain of the endoplasmic reticulum-localized
M1-isoform of the spastin molecule. Together both proteins may
contribute to the shaping of endoplasmic reticulum tubules
(Montenegro et al., 2012). Interestingly, loss of the Drosophila
orthologue of reticulon 2 leads to an expansion of rough endoplasmic reticulum sheets in larval epidermis and to elevated levels
of endoplasmic reticulum stress. Its loss also causes abnormalities
within distal portions of longer motor axons and in their presynaptic terminals, which includes disruption of the smooth endoplasmic
reticulum, microtubules, and mitochondria (O’Sullivan et al.,
2012).
SPAST
The SPAST gene encodes different spastin isoforms with various
functions and a complex subcellular localization pattern. Spastin
acts as a microtubule severing enzyme and cuts microtubules
into short fragments (Blackstone, 2012). It was shown that ATPbound spastin molecules form a hexameric ring, which docks onto
and destabilizes microtubules by pulling them through the central
pore formed by the hexamer (Roll-Mecak and Vale, 2008).
A microtubule interacting and trafficking (MIT) domain present
in all spastin isoforms mediates the recruitment to endosomes
and interaction with ESCRT (endosomal sorting complex
required for transport) proteins that are involved in membrane
remodelling (Hurley and Hanson, 2010). The M1 splice variant
of spastin (M1-spastin) comprises an N-terminal hairpin domain
that associates with the endoplasmic reticulum and
endoplasmic reticulum to Golgi intermediate compartment
(ERGIC) and mediates interaction with atlastins, REEPs, and
reticulons (Sanderson et al., 2006; Park et al., 2010). This
oligomerization may facilitate the membrane-shaping capacities
of the complex, but the precise role of spastin in endoplasmic
reticulum membrane remodelling largely remains unclear (Lumb
et al., 2012).
Mutations in SPAST cause the most frequent form (40%) of
autosomal-dominant pure/uncomplicated HSP (Hazan et al.,
1999). Major symptoms include progressive spastic weakness
and hyperreflexia. Loss of ambulation occurs in 20–25% of the
cases. Individuals may also have increased reflexes in the upper
limbs, but they are rarely tetraspastic. One-third of the patients
have sphincter disturbances. Decreased vibration sense has been
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Figure 4 REEP1 shows membrane-shaping properties. Upper panel: Incubation of REEP1 protein with liposomes induces the formation of
small diameter liposomes indicative of an intrinsic membrane-shaping capacity of the protein. Mutation of hydrophobic residues (I57, F58,
F62, F64) within the hairpin domain impairs the formation of small diameter vesicles as shown by freeze-fracture electron microscopy
(Beetz et al., 2013b). Lower panel: Model summarizing the effect of Reep1 knockout in mice according to Beetz et al. (2013b): loss of
REEP1 in cortical motor neurons results in a reduced complexity of the peripheral endoplasmic reticulum, reflected by a reduced number of
endoplasmic reticulum (ER) cross sections with an increase in the mean length per section.
reported in a substantial number of individuals. However, complicated forms have also been reported (Fink, 2013). Age at onset is
highly variable but most often in young adulthood. The disease
progression is likewise variable, but has been reported to progress
more rapidly in individuals with late onset. Some cases with incomplete penetrance have been reported.
Protrudin/ZFYVE27
Protrudin/ZFYVE27 harbours a hairpin domain and forms complexes with other reticulon domain-containing proteins (Chang
et al., 2013; Hashimoto et al., 2014). A single missense mutation
was identified in a family with HSP and the locus was designated
as SPG33 (Mannan et al., 2006). Another study found no functional evidence for pathogenicity of this mutation (Martignoni
et al., 2008), but recently it has been shown that the reported
missense mutation confers an increased susceptibility to endoplasmic reticulum stress (Hashimoto et al., 2014). More data are
needed to clarify the role of protrudin/ZFYVE27 in human axon
degeneration.
Other membrane-shaping proteins
Other proteins without a hairpin domain play a role in shaping intracellular membranes as well. One example is the protein encoded by
the TRK-fused gene (TFG), a coiled-coil domain-containing protein
that functions at sites of vesicle biogenesis on the endoplasmic reticulum, forming a matrix between endoplasmic reticulum exit sites
and the endoplasmic reticulum–Golgi intermediate compartment.
TFG facilitates the assembly of the COPII coat complex, required
for membrane deformation and vesicle biogenesis from the endoplasmic reticulum (Witte et al., 2011). An identical missense mutation (p.Pro285Leu) in TFG was identified in four families with
autosomal-dominant proximal hereditary motor and sensory neuropathy (HMSNP) (Ishiura et al., 2012) and was confirmed in an
independent study (Lee et al., 2013). HMSNP is characterized by
young adult onset of proximal muscle weakness and atrophy, muscle
cramps, fasciculations, and distal sensory impairment. Fragmentation
of the Golgi apparatus was observed in motor neurons from affected
individuals. A different TFG missense mutation was subsequently
identified in autosomal-recessive complicated HSP with optic atrophy
and neuropathy (SPG57) (Beetz et al., 2013a). In this study, TFG
Membrane-shaping disorders
inhibition was shown to slow protein secretion from the endoplasmic
reticulum and to alter endoplasmic reticulum morphology. Disruption
of peripheral endoplasmic reticulum tubules caused a collapse of the
endoplasmic reticulum network onto the underlying microtubule
cytoskeleton.
Another example of a membrane-shaping protein is RAB3GAP2,
a protein of the Rab regulatory complex, which acts as specific
Rab18 guanine nucleotide exchange factor (GEF) (Gerondopoulos
et al., 2014). RAB3GAP2 mutations were involved in autosomalrecessive Warburg Micro syndrome and Martsolf syndrome, two
overlapping complex disorders including progressive spastic paraplegia (Borck et al., 2011; Handley et al., 2013; Novarino et al.,
2014). The RAB3GAP complex localizes to the endoplasmic reticulum and mediates endoplasmic reticulum targeting of RAB18
(Gerondopoulos et al., 2014). Its loss results in altered endoplasmic reticulum structure and suggests that RAB18 effectors may
regulate endoplasmic reticulum tubule tethering and fusion, or
inhibit endoplasmic reticulum sheet extension (Gerondopoulos
et al., 2014). Interestingly, RAB3GAP2—together with several
hairpin-domain containing proteins—was identified in a proteomic
study of protrudin/ZFYVE27 interactors (Hashimoto et al., 2014).
Clinical overlap and allelic
membrane-shaping disorders
Axonopathies show considerable clinical overlap. Although HSP is
a disorder that mainly manifests at the corticospinal tract, the
disease is often accompanied by sensory disturbances.
Conversely, some individuals with FAM134B-associated sensory
neurodegeneration show signs of spasticity suggesting that
upper motor neurons can be involved in the progression of the
disease (Kurth et al., 2009; Aydinlar et al., 2014). Similarly, ATL3
mutations associated with peripheral sensory neuropathy can be
accompanied by spasticity of the legs (Fischer et al., 2014).
Besides this clinical overlap it becomes more evident that several
axonopathies are allelic conditions, i.e. mutations in the same gene
can lead to different disorders (Timmerman et al., 2013). Although
mutations in REEP1 had initially been associated with HSP
(Zuchner et al., 2006), a mutation in the same gene was also
found in pure distal hereditary motor neuropathy (HMN5B) without signs of CNS involvement (Beetz et al., 2012). The majority of
ATL1 mutations results in HSP/SPG3A (Zhao et al., 2001), but
some mutations are exclusively associated with sensory neuropathy type 1 (HSN1D, HSAN1D) (Guelly et al., 2011). With
the use of next generation sequencing technologies even more allelic variants will be detected soon. As a consequence membraneshaping disorders may rather be considered as a continuous
neurodegenerative disease spectrum of long fibre tracts.
Putative downstream effectors
in membrane-shaping disorders
Changes in organelle shape can impact on a multitude of downstream pathways. Neuron death as a final outcome is likely to
Brain 2014: 137; 3109–3121
| 3117
result from the convergence of different pathological processes.
Contact sites between organelles may be one critical bottleneck
because these sites have particular architectural requirements.
Close apposition for example, exists between the endoplasmic reticulum and the plasma membrane (English and Voeltz, 2013a;
Helle et al., 2013) to allow Ca2 + entry, which is fundamental
for excitability, exocytosis, enzyme control, and gene regulation
(Parekh and Putney, 2005). Emptying of intracellular Ca2 + stores
involves STIM proteins in the endoplasmic reticulum membrane,
which can sense a drop in the endoplasmic reticulum Ca2 + concentration. Upon Ca2 + depletion they accumulate at endoplasmic
reticulum/plasma membrane junctions to trigger Ca2 + influx via
store-operated ORAI Ca2 + channels in the plasma membrane,
which are also redistributed to endoplasmic reticulum/plasma
membrane coupling sites (Carrasco and Meyer, 2011). Coupling
of STIM proteins with ORAI1 critically depends on reticulon proteins and disruption of RTN4 was shown to result in loss of endoplasmic reticulum tubulation and caused a redistribution of STIM1
to endoplasmic reticulum sheets (Jozsef et al., 2014).
Reticulon domain proteins may also play a role in maintaining
functional contacts between the endoplasmic reticulum and mitochondria. The uptake of Ca2 + at mitochondria-associated endoplasmic reticulum membranes (MAMs) critically depends on the
correct spacing between both organelles and alterations in membrane-shaping proteins are likely to interfere with endoplasmic
reticulum-mitochondria contacts (Csordas et al., 2010;
Giacomello et al., 2010). The shape of the endoplasmic reticulum
at endoplasmic reticulum–mitochondria contact sites also affects
lipid exchange between both organelles, which is important for
mitochondrial membrane biogenesis (Voss et al., 2012; Raturi
and Simmen, 2013). Moreover, contacts between endoplasmic
reticulum and mitochondria have been shown to play an important role for the biogenesis of autophagosomes under conditions of
nutrient depletion and starvation (Wong and Cuervo, 2010;
Bernard and Klionsky, 2013; Hamasaki et al., 2013).
Extensive membrane exchange for trafficking, lipid transfer, and
protein secretion exists between the Golgi apparatus and endoplasmic reticulum membranes. In line with this, RTN3 overexpression was shown to interfere with both anterograde and retrograde
transport between endoplasmic reticulum and Golgi apparatus
(Wakana et al., 2005). Mutations in hairpin-domain proteins
may also primarily affect the Golgi apparatus as endogenous atlastins and FAM134B have been shown to localize to the Golgi compartment in neurons (Rismanchi et al., 2008; Kurth et al., 2009).
Indeed, acute knockdown of FAM134B in neuronal cells resulted
in structural alterations of the cis-Golgi apparatus (Kurth et al.,
2009).
An open question is how proper spacing and branching of
endoplasmic reticulum tubules may impact on endoplasmic reticulum stress and the unfolded protein response. Exposure of cells to
endoplasmic reticulum stress triggers a massive endoplasmic reticulum expansion (Schuck et al., 2009). This increase in endoplasmic reticulum volume lowers the concentration of folding
intermediates, which may help to reduce the load of misfolded
proteins and protein aggregate formation to support cellular survival (Ron and Walter, 2007; Apetri and Horwich, 2008; Schuck
et al., 2009). Overexpression of RTN1-1C increases the enzyme
3118
| Brain 2014: 137; 3109–3121
activity of the chaperone protein disulphide isomerase that is upregulated during the unfolded protein response and catalyzes correct
protein folding in the endoplasmic reticulum (Bernardoni et al.,
2013). In line with this, ablation of RTN4-A accelerates disease
onset and progression in an amyotrophic lateral sclerosis SOD1
(G93A) transgenic mouse model where endoplasmic reticulum
stress and impaired endoplasmic reticulum chaperone function determines the cellular pathology (Yang et al., 2009). However, the
downstream cascades in membrane-shaping disorders are still
poorly understood and clearly require more attention.
Future perspectives
Although knowledge on shaping disorders is constantly growing
the question why neurons are especially prone to damage remains
unanswered. Is it merely the unique architecture of an extraordinarily long axon that determines a liability to damage? How does
the post-mitotic status of neurons contribute to axonal vulnerability? Since organelles such as endoplasmic reticulum or Golgi apparatus are dispersed and reassembled during mitotic cell division
one might speculate that the constant rearrangement is essential
to maintain cellular homeostasis under varying conditions. Another
enigma is the fact that mutations in the same gene can either
affect axons of the CNS in one patient or result in degeneration
of peripheral neurons in others. An attractive hypothesis is that
individual genetic variants in different genes either prevent or promote neurodegeneration. Addressing the overall ‘mutation-load’ in
axonopathy patients may identify such important genetic modifiers. However, evaluation of risk alleles within the large number
of rare and potentially functional variants in each human genome
remains a challenging task for the future.
Funding
Deutsche Forschungsgemeinschaft (DFG) to I.K. (KU 1587/2-1,
KU 1587/3-1, KU 1587/4-1) and to C.A.H. (HU 800/5-1, RTG
1715, HU 800/6-1, HU 800/7-1).
Acknowledgements
The authors apologize to all colleagues whose work could not be
cited owing to space limitations. We are grateful to the families
who participated in research studies to identify causative genes
and mechanisms in hereditary axon degeneration.
References
Akiduki S, Ikemoto MJ. Modulation of the neural glutamate transporter
EAAC1 by the addicsin-interacting protein ARL6IP1. J Biol Chem 2008;
283: 31323–32.
Apetri AC, Horwich AL. Chaperonin chamber accelerates protein folding
through passive action of preventing aggregation. Proc Natl Acad Sci
USA 2008; 105: 17351–5.
Auer-Grumbach M. Hereditary sensory and autonomic neuropathies.
Handb Clin Neurol 2014; 115: 893–906.
C. A. Hübner and I. Kurth
Aydinlar EI, Rolfs A, Serteser M, Parman Y. Mutation in FAM134B causing hereditary sensory neuropathy with spasticity in a Turkish family.
Muscle Nerve 2014; 49: 774–5.
Barlowe C, Orci L, Yeung T, Hosobuchi M, Hamamoto S, Salama N,
et al. COPII: a membrane coat formed by Sec proteins that drive
vesicle budding from the endoplasmic reticulum. Cell 1994; 77:
895–907.
Beetz C, Johnson A, Schuh AL, Thakur S, Varga RE, Fothergill T, et al.
Inhibition of TFG function causes hereditary axon degeneration by
impairing endoplasmic reticulum structure. Proc Natl Acad Sci USA
2013a; 110: 5091–6.
Beetz C, Koch N, Khundadze M, Zimmer G, Nietzsche S, Hertel N, et al.
A hereditary spastic paraplegia mouse model reveals Reep1-dependent
ER shaping. J Clin Invest 2013b; 123: 4273–82.
Beetz C, Pieber T, Hertel N, Schabhüttl M, Fischer C, Trajanoski S, et al.
Exome sequencing identifies a REEP1 Mutation involved in distal
hereditary motor neuropathy type V. Am J Hum Genet 2012; 91:
139–45.
Beetz C, Schule R, Deconinck T, Tran-Viet KN, Zhu H, Kremer BP, et al.
REEP1 mutation spectrum and genotype/phenotype correlation in
hereditary spastic paraplegia type 31. Brain 2008; 131 (Pt 4): 1078–86.
Bernard A, Klionsky DJ. Autophagosome formation: tracing the source.
Dev Cell 2013; 25: 116–7.
Bernardoni P, Fazi B, Costanzi A, Nardacci R, Montagna C, Filomeni G,
et al. Reticulon1-C modulates protein disulphide isomerase function.
Cell Death Dis 2013; 4: e581.
Bian X, Klemm R, Liu T, Zhang M, Sun S, Sui X, et al. Structures of the
atlastin GTPase provide insight into homotypic fusion of endoplasmic
reticulum membranes. Proc Natl Acad Sci USA 2011; 108: 3976–81.
Bjork S, Hurt CM, Ho VK, Angelotti T. REEPs are membrane shaping
adapter proteins that modulate specific g protein-coupled receptor
trafficking by affecting ER cargo capacity. PLoS One 2013; 8: e76366.
Blackstone C. Cellular pathways of hereditary spastic paraplegia. Annu
Rev Neurosci 2012; 35: 25–47.
Bonifacino JS, Glick BS. The mechanisms of vesicle budding and fusion.
Cell 2004; 116: 153–66.
Borck G, Wunram H, Steiert A, Volk AE, Korber F, Roters S, et al. A
homozygous RAB3GAP2 mutation causes Warburg Micro syndrome.
Hum Genet 2011; 129: 45–50.
Borgese N, Francolini M, Snapp E. Endoplasmic reticulum architecture:
structures in flux. Curr Opin Cell Biol 2006; 18: 358–64.
Byrnes L, Sondermann H. Structural basis for the nucleotide-dependent
dimerization of the large G protein atlastin-1/SPG3A. Proc Natl Acad
Sci USA 2011; 108: 2216–21.
Carrasco S, Meyer T. STIM proteins and the endoplasmic reticulumplasma membrane junctions. Annu Rev Biochem 2011; 80: 973–1000.
Chang J, Lee S, Blackstone C. Protrudin binds atlastins and endoplasmic
reticulum-shaping proteins and regulates network formation. Proc Natl
Acad Sci USA 2013; 110: 14954–9.
Csordas G, Varnai P, Golenar T, Roy S, Purkins G, Schneider TG, et al.
Imaging interorganelle contacts and local calcium dynamics at the ERmitochondrial interface. Mol Cell 2010; 39: 121–32.
Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, et al.
Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol 2012; 259:
1673–85.
de Bot ST, Veldink JH, Vermeer S, Mensenkamp AR, Brugman F,
Scheffer H, et al. ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes. J Neurol 2013; 260: 869–75.
Deutch AY, Hedera P, Colbran RJ. REEPing the benefits of an animal
model of hereditary spastic paraplegia. J Clin Invest 2013; 123:
4134–6.
Di Sano F, Bernardoni P, Piacentini M. The reticulons: guardians of the
structure and function of the endoplasmic reticulum. Exp Cell Res
2012; 318: 1201–7.
Durr A, Camuzat A, Colin E, Tallaksen C, Hannequin D, Coutinho P,
et al. Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia. Arch Neurol 2004; 61: 1867–72.
Membrane-shaping disorders
English AR, Voeltz GK. Endoplasmic reticulum structure and interconnections with other organelles. Cold Spring Harb Perspect Biol 2013a; 5:
a013227.
English AR, Voeltz GK. Rab10 GTPase regulates ER dynamics and
morphology. Nat Cell Biol 2013b; 15: 169–78.
Esteves T, Durr A, Mundwiller E, Loureiro JL, Boutry M, Gonzalez MA,
et al. Loss of association of REEP2 with membranes leads to hereditary
spastic paraplegia. Am J Hum Genet 2014; 94: 268–77.
Evans K, Keller C, Pavur K, Glasgow K, Conn B, Lauring B. Interaction of
two hereditary spastic paraplegia gene products, spastin and atlastin,
suggests a common pathway for axonal maintenance. Proc Natl Acad
Sci USA 2006; 103: 10666–71.
Falk J, Rohde M, Bekhite MM, Neugebauer S, Hemmerich P,
Kiehntopf M, et al. Functional mutation analysis provides evidence
for a role of REEP1 in lipid droplet biology. Hum Mutat 2014; 35:
497–504.
Farese RV Jr, Walther TC. Lipid droplets finally get a little R-E-S-P-E-CT. Cell 2009; 139: 855–60.
Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and
emerging molecular mechanisms. Acta Neuropathol 2013; 126:
307–28.
Fischer D, Schabhuttl M, Wieland T, Windhager R, Strom TM, AuerGrumbach M. A novel missense mutation confirms ATL3 as a gene
for hereditary sensory neuropathy type 1. Brain 2014; 134 (Pt 7):
e286.
Gerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S,
Aligianis I, et al. Rab18 and a Rab18 GEF complex are required for
normal ER structure. J Cell Biol 2014; 205: 707–20.
Giacomello M, Drago I, Bortolozzi M, Scorzeto M, Gianelle A, Pizzo P,
et al. Ca2 + hot spots on the mitochondrial surface are
generated by Ca2 + mobilization from stores, but not by
activation of store-operated Ca2 + channels. Mol Cell 2010; 38:
280–90.
Goizet C, Depienne C, Benard G, Boukhris A, Mundwiller E, Sole G, et al.
REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.
Hum Mutat 2013; 32: 1118–27.
Guelly C, Zhu P-P, Leonardis L, Papic L, Zidar J, Schabhüttl M, et al.
Targeted high-throughput sequencing identifies mutations in atlastin-1
as a cause of hereditary sensory neuropathy type I. Am J Hum Genet
2011; 88: 99–105.
Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N,
et al. Autophagosomes form at ER-mitochondria contact sites.
Nature 2013; 495: 389–93.
Handley MT, Morris-Rosendahl DJ, Brown S, Macdonald F, Hardy C,
Bem D, et al. Mutation spectrum in RAB3GAP1, RAB3GAP2,
and RAB18 and genotype-phenotype correlations in warburg
micro syndrome and Martsolf syndrome. Hum Mutat 2013; 34:
686–96.
Hashimoto Y, Shirane M, Matsuzaki F, Saita S, Ohnishi T, Nakayama KI.
Protrudin Regulates endoplasmic reticulum morphology and function
associated with the pathogenesis of hereditary spastic paraplegia. J Biol
Chem 2014; 289: 12946–61.
Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D,
Artiguenave F, et al. Spastin, a new AAA protein, is altered in the
most frequent form of autosomal dominant spastic paraplegia. Nat
Genet 1999; 23: 296–303.
Helfrich W. Elastic properties of lipid bilayers: theory and possible experiments. Z Naturforsch C 1973; 28: 693–703.
Helle SC, Kanfer G, Kolar K, Lang A, Michel AH, Kornmann B.
Organization and function of membrane contact sites. Biochim
Biophys Acta 2013; 1833: 2526–41.
Hu J, Shibata Y, Voss C, Shemesh T, Li Z, Coughlin M, et al. Membrane
proteins of the endoplasmic reticulum induce high-curvature tubules.
Science 2008; 319: 1247–50.
Hu J, Shibata Y, Zhu P-P, Voss C, Rismanchi N, Prinz W, et al. A class of
dynamin-like GTPases involved in the generation of the tubular ER
network. Cell 2009; 138: 549–61.
Brain 2014: 137; 3109–3121
| 3119
Huang HY, Liu JT, Yan HY, Tsai HJ. Arl6ip1 plays a role in proliferation
during zebrafish retinogenesis. Cells Tissues Organs 2012; 196:
161–74.
Hurley JH, Hanson PI. Membrane budding and scission by the ESCRT
machinery: it’s all in the neck. Nat Rev Mol Cell Biol 2010; 11:
556–66.
Ilegems E, Iwatsuki K, Kokrashvili Z, Benard O, Ninomiya Y,
Margolskee RF. REEP2 enhances sweet receptor function by recruitment to lipid rafts. J Neurosci 2010; 30: 13774–83.
Ishiura H, Sako W, Yoshida M, Kawarai T, Tanabe O, Goto J, et al. The
TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. Am J Hum Genet
2012; 91: 320–9.
Jozsef L, Tashiro K, Kuo A, Park E, Skoura A, Albinsson S, et al. Reticulon
4 Is necessary for endoplasmic reticulum tubulation, STIM1-Orai1 coupling, and store-operated calcium entry. J Biol Chem 2014; 289:
9380–95.
Kasem K, Gopalan V, Salajegheh A, Lu CT, Smith RA, Lam AK. JK1
(FAM134B) gene and colorectal cancer: A pilot study on the gene
copy number alterations and correlations with clinicopathological parameters. Exp Mol Pathol 2014; 97: 31–6.
Khan TN, Klar J, Tariq M, Anjum Baig S, Malik NA, Yousaf R, et al.
Evidence for autosomal recessive inheritance in SPG3A caused by
homozygosity for a novel ATL1 missense mutation. Eur J Hum
Genet 2014; 22: 1180–4.
Klemm RW, Norton JP, Cole RA, Li CS, Park SH, Crane MM, et al. A
conserved role for atlastin GTPases in regulating lipid droplet size. Cell
Rep 2013; 30: 1465–75.
Kong M, Kim Y, Lee C. A strong synergistic epistasis between FAM134B
and TNFRSF19 on the susceptibility to vascular dementia. Psychiatr
Genet 2011; 21: 37–41.
Kornak U, Mademan I, Schinke M, Voigt M, Krawitz P, Hecht J, et al.
Sensory neuropathy with bone destruction due to a mutation in the
membrane-shaping atlastin GTPase 3. Brain 2014; 137 (Pt 3): 683–92.
Kuroda M, Funasaki S, Saitoh T, Sasazawa Y, Nishiyama S, Umezawa K,
et al. Determination of topological structure of ARL6ip1 in cells: identification of the essential binding region of ARL6ip1 for conophylline.
FEBS Lett 2014; 587: 3656–60.
Kurth I, Pamminger T, Hennings J, Soehendra D, Huebner A, Rotthier A,
et al. Mutations in FAM134B, encoding a newly identified golgi protein, cause severe sensory and autonomic neuropathy. Nat Genet
2009; 41: 1179–81.
Lee MC, Miller EA, Goldberg J, Orci L, Schekman R. Bi-directional protein transport between the ER and Golgi. Annu Rev Cell Dev Biol
2004; 20: 87–123.
Lee SS, Lee HJ, Park JM, Hong YB, Park KD, Yoo JH, et al. Proximal
dominant hereditary motor and sensory neuropathy with proximal
dominance association with mutation in the TRK-fused gene. JAMA
Neurol 2013; 70: 607–15.
Liu T, Bian X, Sun S, Hu X, Klemm R, Prinz W, et al. Lipid interaction of
the C terminus and association of the transmembrane segments facilitate atlastin-mediated homotypic endoplasmic reticulum fusion. Proc
Natl Acad Sci USA 2012; 109: E2146–54.
Lui HM, Chen J, Wang L, Naumovski L. ARMER, apoptotic regulator in
the membrane of the endoplasmic reticulum, a novel inhibitor of
apoptosis. Mol Cancer Res 2003; 1: 508–18.
Lumb JH, Connell JW, Allison R, Reid E. The AAA ATPase spastin links
microtubule severing to membrane modelling. Biochim Biophys Acta
2012; 1823: 192–7.
Mannan AU, Krawen P, Sauter SM, Boehm J, Chronowska A,
Paulus W, et al. ZFYVE27 (SPG33), a novel spastin-binding protein,
is mutated in hereditary spastic paraplegia. Am J Hum Genet 2006;
79: 351–7.
Martignoni M, Riano E, Rugarli EI. The role of ZFYVE27/protrudin in
hereditary spastic paraplegia. Am J Hum Genet 2008; 83: 127–8.
McCorquodale D, Ozomaro U, Huang J, Montenegro G, Kushman A,
Citrigno L, et al. Mutation screening of spastin, atlastin, and REEP1 in
hereditary spastic paraplegia. Clin Genet 2011; 79: 523–30.
3120
| Brain 2014: 137; 3109–3121
Montenegro G, Rebelo AP, Connell J, Allison R, Babalini C, D’Aloia M,
et al. Mutations in the ER-shaping protein reticulon 2 cause the axondegenerative disorder hereditary spastic paraplegia type 12. J Clin
Invest 2012; 122: 538–44.
Moss TJ, Andreazza C, Verma A, Daga A, McNew JA. Membrane fusion
by the GTPase atlastin requires a conserved C-terminal cytoplasmic tail
and dimerization through the middle domain. Proc Natl Acad Sci USA
2011; 108: 11133–8.
Muriel M-P, Dauphin Al, Namekawa M, Gervais A, Brice A, Ruberg M.
Atlastin-1, the dynamin-like GTPase responsible for spastic paraplegia
SPG3A, remodels lipid membranes and may form tubules and vesicles
in the endoplasmic reticulum. J Neurochem 2009; 110: 1607–16.
Murphy SM, Davidson GL, Brandner S, Houlden H, Reilly MM. Mutation
in FAM134B causing severe hereditary sensory neuropathy. J Neurol
Neurosurg Psychiatry 2012; 83: 119–20.
Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL,
Heiberg AD, et al. Exome sequencing links corticospinal motor
neuron disease to common neurodegenerative disorders. Science
2014; 343: 506–11.
O’Sullivan NC, Jahn TR, Reid E, O’Kane CJ. Reticulon-like-1, the
Drosophila orthologue of the hereditary spastic paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of
distal motor axons. Hum Mol Genet 2012; 21: 3356–65.
Oertle T, Klinger M, Stuermer CA, Schwab ME. A reticular rhapsody:
phylogenic evolution and nomenclature of the RTN/Nogo gene family.
FASEB J 2003; 17: 1238–47.
Orlacchio A, Kawarai T, Rogaeva E, Song YQ, Paterson AD, Bernardi G,
et al. Clinical and genetic study of a large Italian family linked to
SPG12 locus. Neurology 2002; 59: 1395–401.
Orso G, Pendin D, Liu S, Tosetto J, Moss T, Faust J, et al. Homotypic
fusion of ER membranes requires the dynamin-like GTPase atlastin.
Nature 2009; 460: 978–83.
Parekh AB, Putney JW Jr. Store-operated calcium channels. Physiol Rev
2005; 85: 757–810.
Park S, Zhu P-P, Parker R, Blackstone C. Hereditary spastic paraplegia
proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest 2010; 120:
1097–110.
Park SH, Blackstone C. Further assembly required: construction and dynamics of the endoplasmic reticulum network. EMBO Rep 2010; 11:
515–21.
Pendin D, Tosetto J, Moss TJ, Andreazza C, Moro S, McNew JA, et al.
GTP-dependent packing of a three-helix bundle is required for atlastinmediated fusion. Proc Natl Acad Sci USA 2011; 108: 16283–8.
Praefcke GJ, McMahon HT. The dynamin superfamily: universal membrane tubulation and fission molecules? Nat Rev Mol Cell Biol 2004; 5:
133–47.
Raturi A, Simmen T. Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane
(MAM). Biochim Biophys Acta 2013; 1833: 213–24.
Reid E, Dearlove AM, Osborn O, Rogers MT, Rubinsztein DC. A locus
for autosomal dominant “pure” hereditary spastic paraplegia maps to
chromosome 19q13. Am J Hum Genet 2000; 66: 728–32.
Renvoise B, Blackstone C. Emerging themes of ER organization in the
development and maintenance of axons. Curr Opin Neurobiol 2010;
20: 531–7.
Rismanchi N, Soderblom C, Stadler J, Zhu P-P, Blackstone C. Atlastin
GTPases are required for Golgi apparatus and ER morphogenesis.
Hum Mol Genet 2008; 17: 1591–604.
Roll-Mecak A, Vale RD. Structural basis of microtubule severing by
the hereditary spastic paraplegia protein spastin. Nature 2008; 451:
363–7.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519–29.
Rotthier A, Baets J, Timmerman V, Janssens K. Mechanisms of disease in
hereditary sensory and autonomic neuropathies. Nat Rev Neurol 2012;
8: 73–85.
C. A. Hübner and I. Kurth
Saito H, Kubota M, Roberts RW, Chi Q, Matsunami H. RTP family
members induce functional expression of mammalian odorant receptors. Cell 2004; 119: 679–91.
Sanderson CM, Connell JW, Edwards TL, Bright NA, Duley S,
Thompson A, et al. Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners.
Hum Mol Genet 2006; 15: 307–18.
Scheubert L, Schmidt R, Repsilber D, Lustrek M, Fuellen G. Learning
biomarkers of pluripotent stem cells in mouse. DNA Res 2011; 18:
233–51.
Schuck S, Prinz WA, Thorn KS, Voss C, Walter P. Membrane expansion
alleviates endoplasmic reticulum stress independently of the unfolded
protein response. J Cell Biol 2009; 187: 525–36.
Sharpe HJ, Stevens TJ, Munro S. A comprehensive comparison of transmembrane domains reveals organelle-specific properties. Cell 2010;
142: 158–69.
Shibata H, Yamamoto K, Sun Z, Oka A, Inoko H, Arinami T, et al.
Genome-wide association study of schizophrenia using microsatellite
markers in the Japanese population. Psychiatr Genet 2013; 23:
117–23.
Shibata Y, Hu J, Kozlov M, Rapoport T. Mechanisms shaping the membranes of cellular organelles. Ann Rev Cell Deve Biol 2009; 25:
329–54.
Shibata Y, Voss C, Rist JM, Hu J, Rapoport TA, Prinz WA, et al.
The reticulon and DP1/Yop1p proteins form immobile oligomers in
the tubular endoplasmic reticulum. J Biol Chem 2008; 283:
18892–904.
Südhof TC, Rothman JE. Membrane fusion: grappling with SNARE and
SM proteins. Science 2009; 323: 474–7.
Tang WK, Chui CH, Fatima S, Kok SH, Pak KC, Ou TM, et al. Oncogenic
properties of a novel gene JK-1 located in chromosome 5p and its
overexpression in human esophageal squamous cell carcinoma. Int J
Mol Med 2007; 19: 915–23.
Timmerman V, Clowes VE, Reid E. Overlapping molecular pathological
themes link Charcot-Marie-Tooth neuropathies and hereditary spastic
paraplegias. Exp Neurol 2013; 246: 14–25.
Tu CT, Yang TC, Huang HY, Tsai HJ. Zebrafish arl6ip1 is required for
neural crest development during embryogenesis. PLoS One 2012; 7:
e32899.
Voeltz G, Prinz W, Shibata Y, Rist J, Rapoport T. A class of membrane
proteins shaping the tubular endoplasmic reticulum. Cell 2006; 124:
573–86.
Voss C, Lahiri S, Young BP, Loewen CJ, Prinz WA. ER-shaping proteins
facilitate lipid exchange between the ER and mitochondria in S. cerevisiae. J Cell Sci 2012; 125 (Pt 20): 4791–9.
Wakana Y, Koyama S, Nakajima K, Hatsuzawa K, Nagahama M, Tani K,
et al. Reticulon 3 is involved in membrane trafficking between the
endoplasmic reticulum and Golgi. Biochem Biophys Res Commun
2005; 334: 1198–205.
Wang JL, Tong CW, Chang WT, Huang AM. Novel genes FAM134C,
C3orf10 and ENOX1 are regulated by NRF-1 and differentially regulate neurite outgrowth in neuroblastoma cells and hippocampal neurons. Gene 2013; 529: 7–15.
Wieczorek DF, Hughes SR. Developmentally regulated cDNA expressed exclusively in neural tissue. Brain Res Mol Brain Res 1991;
10: 33–41.
Witte K, Schuh AL, Hegermann J, Sarkeshik A, Mayers JR, Schwarze K,
et al. TFG-1 function in protein secretion and oncogenesis. Nat Cell
Biol 2011; 13: 550–8.
Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 2010; 13: 805–11.
Yamamoto Y, Yoshida A, Miyazaki N, Iwasaki K, Sakisaka T. Arl6IP1 has
the ability to shape the mammalian ER membrane in a reticulon-like
fashion. Biochem J 2014; 458: 69–79.
Yang YS, Harel NY, Strittmatter SM. Reticulon-4A (Nogo-A) redistributes
protein disulfide isomerase to protect mice from SOD1-dependent
amyotrophic lateral sclerosis. J Neurosci 2009; 29: 13850–9.
Membrane-shaping disorders
Yang YS, Strittmatter SM. The reticulons: a family of proteins with diverse functions. Genome Biol 2007; 8: 234.
Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber C, et al.
Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet 2001; 29: 326–31.
Brain 2014: 137; 3109–3121
| 3121
Zimmerberg J, Kozlov MM. How proteins produce cellular membrane
curvature. Nat Rev Mol Cell Biol 2006; 7: 9–19.
Zuchner S, Wang G, Tran-Viet KN, Nance MA, Gaskell PC, Vance JM,
et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 2006; 79: 365–9.