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doi:10.1093/brain/awu287 Brain 2014: 137; 3109–3121 | 3109 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] 3110 | Brain 2014: 137; 3109–3121 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 Brain 2014: 137; 3109–3121 | 3111 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 3112 | Brain 2014: 137; 3109–3121 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 Brain 2014: 137; 3109–3121 | 3113 3114 | Brain 2014: 137; 3109–3121 C. A. Hübner and I. Kurth 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. Brain 2014: 137; 3109–3121 | 3115 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 3116 | Brain 2014: 137; 3109–3121 C. A. Hübner and I. Kurth 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. 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