Download Mutations in cytoplasmic dynein and its regulators

5th Conference on Advances in Molecular Mechanisms Underlying Neurological Disorders
Mutations in cytoplasmic dynein and its regulators
cause malformations of cortical development and
neurodegenerative diseases
Joanna Lipka*†, Marijn Kuijpers*, Jacek Jaworski† and Casper C. Hoogenraad*1
*Division of Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands, and †International Institute of
Molecular and Cell Biology, 02-109 Warsaw, Poland
Abstract
Neurons are highly specialized for the processing and transmission of electrical signals and use cytoskeletonbased motor proteins to transport different vesicles and cellular materials. Abnormalities in intracellular
transport are thought to be a critical factor in the degeneration and death of neurons in both the central
and peripheral nervous systems. Several recent studies describe disruptive mutations in the minus-enddirected microtubule motor cytoplasmic dynein that are directly linked to human motor neuropathies,
such as SMA (spinal muscular atrophy) and axonal CMT (Charcot–Marie–Tooth) disease or malformations of
cortical development, including lissencephaly, pachygyria and polymicrogyria. In addition, genetic defects
associated with these and other neurological disorders have been found in multifunctional adaptors that
regulate dynein function, including the dynactin subunit p150Glued , BICD2 (Bicaudal D2), Lis-1 (lissencephaly
1) and NDE1 (nuclear distribution protein E). In the present paper we provide an overview of the diseasecausing mutations in dynein motors and regulatory proteins that lead to a broad phenotypic spectrum
extending from peripheral neuropathies to cerebral malformations.
Introduction
Intracellular cargo transport is driven by myosin, kinesin
and dynein motor proteins that can move directionally along
actin filaments and microtubules. Myosins use actin filaments
for cargo transport, whereas both dyneins and kinesins use
microtubules to drive, respectively, minus-end-directed or
plus-end-directed transport [1,2]. Because of their size and
highly polarized structure, neuronal cells rely heavily on this
transport system. Many studies have shown the fundamental
roles of all three motor families in neuron development,
morphology, survival and function [2]. On the other hand,
defects or misregulation of the neuronal transport system
have very adverse effects. Emerging evidence suggests both
a direct and indirect role for cargo transport in neuronal
pathogenesis. Impairment of axonal transport, for instance,
is a common factor in many neurodegenerative diseases, such
as Huntington’s, Parkinson’s and Alzheimer’s diseases [3–
5]. Dysfunction of mitochondrial transport in axons is a
pathogenic event correlated with many neurodegenerative
diseases [6–8]. Direct evidence supporting the involvement
of motor proteins in neurodegenerative diseases comes from
Key words: Bicaudal D2 (BICD2), dynactin, dynein, lissencephaly 1 (Lis-1), neurodegenerative
disease, nuclear distribution protein E (NDE1), nuclear distribution protein E-like (NDEL1).
Abbreviations used: AAA, ATPase associated with various cellular activities; ALS, amyotrophic
lateral sclerosis; BICD, Bicaudal D; CAP-Gly, cytoskeleton-associated protein-glycine-rich; CMT,
Charcot–Marie–Tooth; DCSMA, dominant cogenital spinal muscular atrophy; DNCT, dynactin;
DYNC1H1, dynein cytoplasmic heavy chain 1; DYNC2H1, dynein cytoplasmic heavy chain 2;
EB1, end-binding protein 1; HSP, hereditary spastic paraplegia; ID, intellectual disability; LED,
lower extremity predominance; Lis-1, lissencephaly 1; Loa, legs at odd angles; MND, motor
neuron disease; NDE1, nuclear distribution protein E; NDEL1, NDE1-like; SMA, spinal muscular
atrophy.
1
To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2013) 41, 1605–1612; doi:10.1042/BST20130188
genetic studies identifying mutations in genes involved in the
microtubule tracks or neuronal transport components [4,9].
In the present review we focus on human mutations in the
minus-end-directed microtubule motor cytoplasmic dynein
and its regulatory proteins that are directly linked to various
neurological diseases.
Cytoplasmic dynein structure and function
Dynein proteins are large multi-subunit motor complexes
that produce force towards the minus-ends of microtubules.
Dynein motors play a role in many processes, ranging from
ciliary and flagellar beating, intraflagellar and intracellular
transport, mitosis and directed cell movement [10–12].
Axonemal dyneins function as molecular engines for ciliary
and flagellar movement, whereas cytoplasmic dyneins are
responsible for a wide variety of basic cellular functions, such
as the movement of organelles, transport of vesicles, proteins
and mRNA, maintenance of the Golgi apparatus, endosome
recycling, cytoskeletal reorientation and the positioning of
the mitotic spindle [13–15]. Cytoplasmic dynein (from now
on called dynein) also has neuron-specific functions and
is particularly involved in neuronal migration, retrograde
axonal transport and polarized trafficking into dendrites [16–
18].
Dynein has a molecular mass of approximately 1.5
MDa, comprises several different subunits and contains
two identical copies of the heavy-chain polypeptide as the
largest subunit (>500 kDa) (Figure 1). The heavy chain is
a member of the AAA + (ATPase associated with various
cellular activities) ATPase superfamily. The C-terminus
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Figure 1 The cytoplasmic dynein complex and its regulators
The dynein molecule (yellow) is a complex of heavy chains (HC),
intermediate chains (IC), light intermediate chains (LIC) and light
chains (LC8, LC7, TCTex). Dynein is bound to the dynactin complex
(green) through interactions between the IC and the p150Glued
subunit of dynactin. The p150Glued subunit also binds cargo vesicles
and microtubules. Another prominent dynactin component is the
actin-related protein Arp1, which associates with membranous cargo
via interaction with spectrin. Other dynein regulators are BICD2, Lis-1,
NDE1 and NDEL1 (blue) that bind the dynein complex either by direct
interaction through dynein or indirectly via dynactin.
known for its involvement in the human disease lissencephaly
[26]. Recent studies found that Lis-1 is necessary for clamping
dynein to the microtubule and initiating dynein-driven
motility [27], whereas NDE proteins are thought to tether
Lis-1 to dynein [28]. Despite their broad involvement in
dynein functions, the precise mechanistic action of dynein
regulators remain poorly understood. Many dynein-driven
processes require the action of these adaptor proteins and,
especially in the case of dynactin and Lis-1, inhibition or
depletion often results in phenotypes similar to that of a
complete loss of dynein function.
Mutations in dynein heavy chain
(DYNC1H1)
consists of six AAA + ring-shaped modules, essential for
ATP hydrolysis, and a 15 nm stalk domain (amino acids
3188–3498), which is responsible for microtubule binding and
generating movement along the microtubule [19] (Figure 1).
Dynein cargo binding is thought to be mediated by five other
accessory subunits: intermediate chains, light intermediate
chains and three light chains, which all associate at the Nterminus (amino acids 0–1400) of the heavy chain (Figure 1).
Besides the dynein core complex, other proteins regulate
dynein function and localization [10]. The best characterized
dynein regulators are the dynactin complex, BICD2 (Bicaudal
D2), Lis-1 (lissencephaly 1), NDE1 (nuclear distribution
protein E) and NDEL1 (NDE1-like). The dynactin complex
(its name is derived from dynein activator [20]) binds
to the dynein intermediate chain, mediates the dynein–
cargo interaction and facilitates dynein-driven transport by
providing additional microtubule binding via the CAP-Gly
(cytoskeleton-associated protein-glycine-rich) domain of the
p150Glued subunit [21] (Figure 1). Like dynactin, the coiledcoil protein BICD is proposed to play a role in dynein–
cargo binding [22], although several studies suggest a role
in the regulation of dynein movement [23,24]. Lis-1 binds
directly to the dynein heavy chain between the ATPase and
microtubule-binding domains of dynein [25] and is best
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Authors Journal compilation The cytoplasmic dynein complex is present in many different
cell types, also in neurons both during development and in
the mature brain. In neuronal cells it is the main molecular
motor necessary for retrograde axonal transport of cellular
material, such as RNA particles, neurofilaments, vesicles,
mitochondria and signalling complexes [29,30]. Moreover,
dynein is also known to be involved in polarized trafficking
and specifically transports proteins and vesicles in dendrites
[31–33]. Most functional studies focus on the cytoplasmic
dynein complex containing dynein heavy chain DYNC1H1
(MIM 600112), but evidence suggests that a second
cytoplasmic dynein complex, cytoplasmic dynein 2, consists
of a distinct heavy chain, DYNC2H1, which is mainly present
in ciliated tissues [34,35]. Human mutations in DYNC2H1
have been linked to many ciliopathies, particularly SRPS
(short-rib polydactyly syndrome) disorders, which are
characterized by short ribs, frequent polydactyly and other
skeletal malformations [36].
Mutations in the DYNC1H1 gene result in peripheral
nervous system disorders, such as axonal Charcot–Marie–
Tooth disease (CMT2), affecting both motor and sensory
neurons and leading to muscle weakness and atrophy [37],
and SMA (spinal muscular atrophy) with LED (lower
extremity predominance), affecting motor neurons and
causing progressive muscle degeneration and weakness
[38]. DYNC1H1 mutations are also linked to severe ID
(intellectual disability) with variable neuronal migration
defects [39] (Table 1). Both CMT2 and SMA–LED show
partial phenotype overlap and many disease characteristics
observed in human patients are similar to those observed
in mice with hypomorphic mutations in the Dync1h1 gene,
such as Loa (legs at odd angles), Cra1 (cramping 1) and
Swl (sprawling) mice [2]. In these mutant mice either lateonset and slowly progressive degeneration of motor neurons
and/or an early-onset sensory neuropathy is observed
[40]. Most of the mutations in cytoplasmic dynein heavy
chain 1 in both humans and mice are localized within
the homodimerization tail domain (Figure 2), suggesting
that the genetic alterations could impair the processivity
of the dynein complex. In vitro studies with dynein
purified from Loa mutant mice [41] and fibroblasts of a
5th Conference on Advances in Molecular Mechanisms Underlying Neurological Disorders
Table 1 Human mutations in dynein subunits and regulators cause neurological disorders
CC, coiled coil; FBD, fetal brain disruption; fs, frameshift; FTD, frontotemporal dementia; MCD, malformation of cortical development; MHAC,
microhydranencephaly; PS, Perry syndrome.
Gene
DYNC1H1
DCNT1
BICD2
NDE1
Mutation in protein
Location
Disease
Reference(s)
H306R
CC
CMT2
[37]
E1518K
H3822P
I584L
Motor domain
Motor domain
CC
ID
ID
SMA-LED
[39]
K671E
Y970C
659–662
CC
CC
CC
SMA-LED
SMA-LED
MCD
K129I
K3336N
R3384Q
Tail region
Stalk
Stalk
MCD
MCD
MCD
R1567Q
R3344Q
R1962C
Linker
Stalk
AAA1
MCD
MCD
MCD
K3241T
R3344Q
G59S
Stalk
Stalk
CAP-Gly
MCD
MCD
MND
G71A
G71R
CAP-Gly
CAP-Gly
PS
PS
G71E
T72P
Q74P
CAP-Gly
CAP-Gly
CAP-Gly
PS
PS
PS
S107L
I189F
R501P
CC1
CC1
CC2
DCSMA
DCSMA
DCSMA
[67–69]
K508T
Q774G
K90R
CC2
CC3
CC1
HSP
DCSMA
DCSMA
[67]
[68]
N188T
T703M
A29fs
CC1
CC3
CC1
DCSMA
DCSMA
Microcephaly
[69]
[79]
P229fs
L245fs
R44stop
C-terminus
C-terminus
CC2
Microcephaly
Microcephaly with lissencephaly
Microcephaly with FBD
[79,80]
[80]
[81]
Microcephaly with FBD
MHAC
[78]
Deletion
Deletion
patient carrying the I584L substitution [38] have provided
experimental evidence for this model. Loa mutant dynein
shows decreased average run lengths, increased affinity for
ATP and increased lateral stepping [41], whereas a decrease
in the affinity of the dynein complex for microtubules
during ATP hydrolysis was observed in the I584L mutant
[38]. These studies indicate an important role for the tail
domain in regulating the motor domain activity. It has
been proposed that dynein could exist in a head-to-tail
conformation, which could negatively regulate its offloading
to the cortex [42]. The data suggest that the dynein mutation
impairs motor domain co-ordination, which may result in
reduced dynein-driven retrograde transport [43]. It has also
been shown that DYNC1H1 mutations lead to mitochondrial
[38]
[46]
[51]
[53]
morphological abnormalities [44], and inhibit retrograde
transport of survival factors [45]. Until recently DYNC1H1
mutations were primarily found associated with neuropathy.
A new study reported nine new DYNC1H1 mutations in 11
individuals (eight sporadic cases plus two brothers and their
mother) diagnosed with wide-range malformations of cortical
development [46] (Table 1). Here, mutations in DYNC1H1
cause cortical malformations characterized by posterior
pachygyria and/or other abnormalities, such as microcephaly
and nodular heterotopia. Some of the DYNC1H1 alterations
encoded, such as K3336N and R3384Q, were located in the
stalk domain (Figure 2) and showed reduced microtubule
binding in in vitro co-pelleting assays [46]. In the future,
it will be intriguing to find out the various molecular
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Figure 2 Schematic overview of the structure of human dynein and its regulators with mapped mutations
Domains of the proteins DYNC1H1, p150Glued (DCNT1), BICD2 and NDE1 are colour-coded: CC (coiled coil; green), AAA
domains (blue), linker (yellow); stalk region (dark green) and CAP-Gly domain (grey). Positions of the mutations are marked
with a black (mutations described in human patients) or red (mutations in mice) asterisk. The black arrowheads represent
deletions, duplications or splice-site mutations.
and cellular mechanisms by which disease-related dynein
mutations disrupt neuronal functions.
Mutations in the dynactin subunit
p150Glued (DNCT1)
Dynactin was found as an activator of dynein-mediated
vesicle transport in vitro [20] and, similar to dynein, dynactin
participates in transport of several intracellular organelles
including endosomes, lysosomes and Golgi membranes.
Dynactin helps to link dynein to cargoes, increases dynein
processivity and initiates dynein-driven cargo transport in
axons [10]. The dynactin complex has a molecular mass of
1 MDa and consists of several subunits, including the largest
subunit of dynactin, p150Glued , encoded by DNCT1 (dynactin
1 gene) [21] (Figure 1). p150Glued interacts directly with
microtubules, the DIC (dynein intermediate chain), other
components of the dynactin complex [21], potential cargo
adaptors [33,47] and microtubule plus-end tracking proteins
[48]. Data suggest that the CAP-Gly domain of p150Glued ,
responsible for interactions with microtubules, is required
for microtubule organization, but is not necessary for cargo
transport [49,50].
Several mutations have been described in the DNCT1
gene (MIM 601143), some of which are associated with
neurodegenerative disorders such as slowly progressing
lower MND (motor neuron disease) and Perry syndrome
(Figure 2 and Table 1). A mutation in DNCT1 was described
by Puls et al. [51], who reported a heterozygous missense
mutation leading to the p150Glued -G59S substitution in
patients with distal spinal and bulbar muscular atrophy, a
slowly progressing autosomal-dominant MND with early
adulthood onset. This finding triggered the search for
DNCT1 mutations segregating with ALS (amyotrophic
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Authors Journal compilation lateral sclerosis). Although some missense mutations were
identified in ALS patients, recent studies found that some
of them could also be detected in healthy subjects [52]. This
suggests that none of the identified ALS-related mutations
are causative and all genetic variations identified so far
should be considered potential risk factors for ALS. Several
missense mutations in DNCT1 were described in Perry
syndrome patients [53] (Table 1). Perry syndrome is a rapidly
progressive autosomal-dominant neurodegenerative disorder
with mid-age onset and is characterized by parkinsonism
with TDP-43 (transactive response DNA-binding protein
43 kDa) proteinopathy in the extrapyramidal system. The
p150Glued -Q74P mutation has been shown to disrupt both
the microtubule and EB1 (end-binding protein 1)-binding
activities of the CAP-Gly domain [54] and could not
restore normal microtubule dynamics in cultured DRG
(dorsal root ganglion) neurons [55]. The p150Glued -G59S
substitution in the CAP-Gly domain is the best-studied
DNCT1 mutation. Experiments using in vitro cultured cells
showed that this particular substitution results in decreased
binding of mutated dynactin to microtubules and EB1,
impairment of endogenous dynactin function, and aggregate
formation which induced neuronal cell death [56]. The
p150Glued -G59S heterozygous knockin mice develop slowly
progressing MND-like pathology, including motor neuron
death [57], whereas the p150Glued heterozygous knockout
mice have no apparent neurodegenerative phenotype,
suggesting that MND is not caused by a loss-of-function
phenotype. Yet it is unclear how p150Glued -G59S exerts
such effects, since no aggregates were observed in p150Glued G59S heterozygous knockin mice, and high instability of
mutated p150Glued was reported [57]. It should be noted,
however, that Chevalier-Larsen et al. [58] did not observe
p150Glued -G59S aggregates in an independent transgenic
line, which still displayed obvious axonal pathology. In
5th Conference on Advances in Molecular Mechanisms Underlying Neurological Disorders
these motor neurons, abnormalities in the enlargement and
proliferation of lysosomes and lipofuscin granules have been
observed, suggesting alterations in the cellular degradative
pathway [59]. Thus, although several DNCT1 mutations
have been identified in various neurodegenerative diseases,
the precise cause of their pathological effects remains a
puzzle.
Mutations in BICD2
A well-studied group of dynein regulatory proteins is
the evolutionarily conserved BICD family [60]. BICD,
meaning ‘two tails’, was first identified in Drosophila through
genetic screens in which mutants show abnormal anteriorto-posterior body patterning [61]. More recent studies
showed that BICD is an essential factor in oogenesis
and embryogenesis by controlling dynein-mediated mRNA
transport [62]. Its highly similar mammalian homologues,
BICD1 and BICD2, have been best characterized for their
involvement in the transport of Rab6-positive secretory
vesicles [63,64], although they also contribute to other
dynein-mediated processes, including nuclear positioning
and lipid droplet trafficking [58,65]. The C-terminal part
of BICD contains the cargo-binding domain (RAB6A
and RANBP2), whereas the N-terminal domain binds to
the dynein–dynactin motor complex [66], promotes the
interaction between dynein and dynactin [24] and induces
microtubule minus-end-directed transport [23].
Recent studies describe various mutations in the BICD2
gene (MIM 609797) in patients with DCSMA (dominant
cogenital spinal muscular atrophy) with LED. These patients
are characterized by non-progressive congenital or earlyonset lower-limb-predominant weakness, which often results
in significant mobility impairment. Three independent
groups reported on the link between BICD2 mutations
and DCSMA (Table 1). First, Oates et al. [67] reported
several missense mutations in BICD2 in patients affected
with DCSMA or DCSMA with upper motor neuron features,
or HSP (hereditary spastic paraplegia). Secondly, Peeters
et al. [68] found mutations in BICD2 in independent
Bulgarian families with autosomal-dominant proximal SMA.
The clinical feature of the patient with the BICD2-Q774G
mutation in the C-terminal part of the protein was very
similar to that of patients with the N-terminal BICD2-S107L
mutation. Thirdly, Neveling et al. [69] described four BICD2
mutations in Dutch and Canadian families afflicted with
autosomal-dominant SMA, with weakness and atrophy of
proximal and distal muscles mainly of the legs. Interestingly,
the sites of the single-amino-acid subsitutions are scattered
throughout the length of the BICD2 protein (Figure 2),
and occur in regions that are involved in cargo binding or
the dynein–dynactin interaction. It is plausible that BICD2
disease mutations may change the binding to Rab6 cargo
or dynein–dynactin, and in this way alter dynein-mediated
processes in motor neurons. Some experimental evidence
exists: BICD2-R501P and BICD2-S107L mutants increase
dynein–dynactin binding and the BICD2-Q774G mutant
decreases Rab6 binding [67,68]. Moreover, overexpression
of various BICD2 mutants disrupt Golgi morphology
[68,69], one of the hallmarks of altered dynein activity
[70]. Although BICD2 mutations are linked to SMA with
dominant inheritance, it is not clear whether the alterations in
BICD2 lead to gain-of-function or dominant-negative lossof function effects. Studies suggest that chronic impairment
of the dynein–dynactin function in transgenic mice by
expression of the N-terminal part of BICD2, despite obvious
features of dynein failure, does not lead to signs of motor
neuron degeneration [71]. These data suggest that DCSMA
alterations in BICD2 are gain-of-function mutations, which
could be in line with functional studies in Drosophila,
showing that dominant BICD2 mutations produce more
severe phenotypes compared with loss-of-function mutants
[61,72].
Mutations in Lis-1 and NDE1
Lis-1 (also known as PAFAH1B1, MIM 607432) and NDE1
(MIM 609449) are important neuronal regulators of dyneinmediated processes [10,26]. Lis-1 encodes a 45 kDa protein
containing a dimerization domain at the N-terminus and a
β-propeller domain that binds dynein at the C-terminus. It
is clear that Lis-1 influences dynein function, but the exact
mechanism is still a matter of debate [26–28]. Mutations in
the Lis-1 gene result in lissencephaly, a neurodevelopmental
disease characterized by absence or severe reduction of brain
gyri, and abnormal cortex lamination and thickness. Over
40 % of isolated lissencephaly and 100 % of MDS (Miller–
Diecker syndrome) patients have either point mutations in
Lis-1 (e.g. causing an H149R substitution or Arg273 stop
codon insertion) or deletions of Lis-1 [73,74]. Mice models
with reduced Lis-1 expression also show severe neuronal
migration defects, suggesting that the lowered dosage of
Lis-1 affects either neuroprecursor divisions or neuronal
migration, or both [26,75]. Interestingly, recently several cases
were described with microduplications of Lis-1-containing
fragments [76,77], leading to some brain malformations as
well as psychomotor and growth retardation. The strongest
phenotypes were observed with larger duplications, which
included Lis-1 and adjacent genes [77].
Genome-wide linkage and sequencing studies identified
mutations in the NDE1 gene in patients with a common
feature of microcephaly (Figure 2 and Table 1). Unlike in
lissencephaly, microcephaly is characterized by reduced brain
size and mental retardation. Guven et al. [78] identified a
homozygous deletion in exon 2 of the NDE1 gene, which
contains the initiation codon and most probably results in
a null allele. Bakircioglu et al. [79] and Alkuraya et al. [80]
found distinct homozygous frameshift mutations in NDE1
and showed that the truncated mutant proteins failed to bind
to the dynein complex. Paciorkowski et al. [81] describe
two patients with inherited deletions of the entire NDE1
gene on one allele combined with a frameshift mutation or
nonsense mutation (R44stop) in the non-deleted NDE1 gene.
Depletion of the Nde1 gene in mice leads to a small brain,
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mental retardation and mild neuronal migration defects [80].
Therefore the various genetic alterations in the Lis-1 and
NDE1 genes described in lissencephaly and microcephaly
patients are probably due to lack of protein function.
Discussion
Loss-of function experiments in flies and mice demonstrate
that dynein-mediated processes are crucial for a large range
of cellular processes, but in neuronal cells dynein function
is mainly linked to neuronal migration processes, axonal
transport, dendrite development and synapse formation
[2,10,12]. The recently described dynein mutations in humans
strongly support the view that the dynein motor complex
is crucial for proper neuronal migrations, differentiation
and maintenance. The genetic alterations in dynein and its
regulators are associated with various neurodevelopmental
and neurodegenerative diseases, particularly SMA, axonal
CMT disease, PS and cortical malformations, such as
lissencephaly and microcephaly (Table 1). In future work,
it will be essential to first advance our understanding of how
dynein functions with its regulatory proteins under nonpathological conditions. We also need to investigate whether
specific disease mutations affect particular dynein-mediated
processes. We postulate that alteration of distinct dynein
pathways may cause impaired development and function of
specific neuronal populations in the central and peripheral
nervous systems and may therefore lead to unique clinical
characteristics. Genetic mutations in animal models often lead
to phenotypes similar to the human disease and will provide
more insight into the molecular basis of dynein function in
both normal and disease states. Moreover, combining the
genetics data with functional in vitro assays will lead to a
much better clinical classification of dynein-related disorders.
It will also be important to look for alterations in other
dynein-interacting partners, including dynein subunits or
dynein regulators, such as dynactin subunits, RZZ (ROD–
ZW10–Zwilch) or spindly. These genes might represent good
candidates for the still many unsolved cases of MND and/or
other developmental or neurological disorders.
Funding
J.L. is supported by the International PhD Projects Programme of the
Foundation for Polish Science (studies of nucleic acids and proteins:
from basic to applied research) co-financed by the European Union
Regional Development Fund. This work is further supported by
the Netherlands Organization for Scientific Research [NWO-ALWVICI and NWO-CW-ECHO (to C.C.H.)], the Netherlands Organization
for Health Research and Development [ZonMW-VIDI and ZonMWTOP (to C.C.H.)], the European Molecular Biology Organization
Young Investigators Program [EMBO-YIP (to C.C.H.)] and ERA-NET
NEURON/06/2011 ‘AMRePACELL’ [co-financed by NCBiR (to J.J.)].
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Received 13 August 2013
doi:10.1042/BST20130188