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DOI 10.1007/s10048-010-0239-4
REVIEW ARTICLE
Received: 17 December 2009 / Accepted: 24 February 2010 / Published online: 27 March 2010
# Springer-Verlag 2010
Introduction
Angiogenin
276
RNA transcription
regulation
ANG
rRNA, tiRNA
RNA transcription
RNA
splicing
ELP3
RNA post-transcriptional
processing/editing
RNA
RNA translation RNA
transport regulation
degradation
Maturation mRNA
RNA helicase
mRNA
SMN
mRNA
mRNA
rRNA, mRNA
Splicing inhibitor
tRNA RNase
Initiator
mRNA
Repressor
mRNA
mRNA
SETX
TARDBP mRNA
Initiator
tRNA
mRNA
mRNA
mRNA
Elongator protein 3
The Elongator protein 3 (ELP3) gene has been associated
with an increased susceptibility to sporadic ALS (SALS)
[190] with risk-associated ELP3 alleles correlating with
lower ELP3 expression in human brain tissues [190].
Supporting this association, two loss-of-function mutations
in the Drosophila ELP3 result in abnormal axonal targeting
and synaptic development. Additionally, ELP3-knockdown
in zebrafish-embryos results in shortening and abnormal
branching of motor neurons [190]. Lastly, silencing of
ELP3 in mice results in delayed migration and impairs the
branching of projection neurons [50].
ELP3 is part of the Elongator complex, also known as
holo-Elongator [61]. Elongator is a component of the RNA
polymerase II complex and consists of a core unit of ELP1,
ELP2, and ELP3 and a smaller unit of ELP4, ELP5, and
ELP6 [230]. Elongator can acetylate histone H3 and to a
lesser extent H4 to make DNA accessible for transcription
[229]. In addition, Elongator is also necessary for posttranscriptional processing of tRNA and ELP1 to ELP3 are
especially important for uridine modification at the wobble
position in tRNA [88]. Interestingly, mutations in IkB
kinase complex-associated protein, a component of Elongator and a homologue of ELP1 in humans, lead to the
development of familial dysautonomia, a hereditary sensory
and autonomic neurodegenerative disease [2].
277
278
Senataxin
Mutations in the senataxin (SETX) gene result in an
autosomal dominant form of juvenile ALS [36], with slow
progressive distal muscle weakness and an onset prior to
25 years of age. In addition, a novel mutation in SETX was
recently identified in a Chinese patient with SALS [242].
Mutations in SETX were originally reported in another
neurodegenerative disease called ataxia-oculomotor apraxia
type 2 (AOA2) [142]. AOA is an autosomal recessive disease
characterized by a slowly progressive degeneration of the
cerebellum, spinal cord, and peripheral nerves, causing ocular
apraxia, cerebellar ataxia, and sensory-motor neuropathy. To
date more than 50 mutations in AOA patients have been
reported [4, 5, 7, 51, 64, 142, 177, 207].
SETX encodes a 302.8-kDa protein consisting of 2,677
amino acids that is ubiquitously expressed [36, 142]. SETX
is diffusely present in the cytoplasm and discrete regions in
the nucleus [37]. The C terminus of SETX contains a
classical seven-motif domain characteristic for RNA/DNA
helicases. DNA helicases can unwind long double-stranded
DNA, while RNA helicases have the ability to unwind
folded RNAs and modify RNARNA interactions. RNA
helicases are frequently found in large ribonucleoprotein
complexes with a generic catalytic core and a specific
external surface. In comparison with DNA helicases,
processive unwinding activity of RNA helicases is uncommon since continuous double-stranded RNA is rare. In
general, helicases maintain the genome integrity and are
involved in many processes including replication, transcription, ribosome biogenesis, pre-mRNA editing and splicing,
RNA export to the cytoplasm, translation initiation and
termination, RNA degradation, organelle gene expression,
recombination, repair, and virus propagation [85, 204].
Helicases could potentially function in these processes by
modification of protein interactions or conformations, or as
energy-dependent enzymes to drive reactions [204].
SETX has strong homology to regulator of nonsense
transcripts-1 (RENT1 or Upf1), Immunoglobulin Mubinding protein 2 (IGHMBP2) and splicing endonuclease
1 (Sen1p), all involved in RNA processing. RENT1/Upf1 is
involved in mRNA nuclear export and nonsense-mediated
mRNA decay. Inhibition of RENT1/Upf1 expression results
in abrogation of both nonsense-mediated mRNA decay and
nonsense-mediated altered splicing [136], which alters gene
expression by affecting the amount of cytoplasmic mRNA
[9]. IGHMBP2 is a 993 amino acid protein that is
ubiquitously expressed, predominantly in the cytoplasm,
279
280
Additional evidence
Apart from the six genes discussed, there is additional
support for a role of RNA processing in ALS. One example
comes from peripherin (PRPH), a type II neuronal
intermediate filament. Currently, only two mutations have
been described in SALS: a 228delC frame shift mutation
predicting a truncated PRPH species of 85 amino acids and
a homozygous D141Y mutation [79, 124]. The mutant
proteins disrupt assembly of the neurofilament network and
are aggregation-prone. Significant elevations of PRPH have
been reported in ALS cervical and lumbar spinal cords
[196]. Furthermore, over-expression of PRPH slows down
the axonal transport of neurofilamental proteins, results in
intermediate filament (IF) inclusions and causes death of
motor neurons [15, 138, 167]. Particularly interesting are
the three peripherin isoforms generated by alternative
splicing in mice: Per 58, Per 56, and Per 61. One of the
isoforms, Per 61, is neurotoxic and induces motor neuron
degeneration [168]. A novel PRPH transcript that results in
a 28-kDa splice isoform has been identified as well [232].
This isoform is normally expressed at low levels, but upregulated in ALS patients and is able to induce aggregation.
PRPH is known to co-localize with TDP-43 in round
inclusions [175], and since TDP-43 acts as a regulator of
alternative splicing, these splicing abnormalities could be
related to TDP-43 dysfunction.
In addition, proteins involved in RNA transport (e.g.,
dynein, dynactin (DCTN1), and kinesin-associated protein
3 (KIFAP3)) have been shown to have a role in ALS
pathogenesis [22, 38, 97, 137, 162]. Dynein is the major
motor driving retrograde transport, but is also essential for
ER- to Golgi trafficking, endosome, and lysosome motility
and spindle assembly [38]. Furthermore, dynein may remove
misfolded or degraded proteins from the cell periphery and
transport them to the cell body for degradation [38].
Noteworthy is dyneins role as the motor driving the minus
end-directed movement of RNA granules along microtubules
[38, 97]. Many of these mRNAs encode cytoskeletal proteins
involved in axon regeneration, including -actin, tau, and
neurofilament subunits [162]. Dynein requires the accessory
activator complex dynactin for most of these functions
possibly acting as an adaptor for dynein, linking the motor
to membrane-bound vesicles and organelles [228].
Mutations in dynactin have been detected in patients
with neurodegenerative disorders. A G59S mutation, which
is predicted to distort the folding of dynactins microtubulebinding domain was present in a family with slowly
281
progressive lower motor neuron disease [163]. Heterozygous missense mutations of the DCTN1 gene have also
been identified in a single SALS case (T1249I), an
individual with familial ALS (M571T), and two FALS
patients along with two unaffected relatives (R785W)
[147]. Lastly, a heterozygous R1101K mutation of the
p150 subunit of dynactin has been reported in a family with
ALS and co-occurrence of FTLD [146]. In autopsies from
patients with ALS, DCTN1 is markedly down-regulated in
residual motor neurons and appears to be an early sign of
degeneration [92]. Over-expression of the p150 subunit of
dynactin in cell cultures abolishes the association between
aggregation-prone SOD1 mutants and the dynein/dynactin
complex, and decreases inclusion formation and improves
cell survival [195]. Inhibition of the dynein/dynactin
complex leads to focal accumulation of neurofilaments
within axonal neurites and causes neurite retraction [145],
stressing the importance of the dynein/dynactin complex in
neurons. Mice with neuron-specific expression of Bicaudal
D2 N terminus to impair dynein/dynactin function do not
develop signs of motor neuron degeneration or motor
abnormalities [208]. However, mice expressing mutant
dynactin p150 demonstrate defects in vesicular transport
in cell bodies of motor neurons, axonal swelling, and axoterminal degeneration [115]. Over-expression of dynamitin
to disassemble dynactin in mice, causes late-onset progressive motor neuron degeneration with decreased strength
and endurance, and denervation of muscles [116].
A SNP (rs1541160) located within the KIFAP3 gene was
found to associate with survival of SALS in a genome-wide
association study [117]. Homozygosity for the favorable
allele results in a 14-month survival advantage and
correlated with reduced expression of the KIFAP3 gene.
Kinesins are a family of microtubule-binding proteins that
act as motors for transport of vesicles, organelles, RNA,
and protein complexes [22, 74, 87, 97, 137, 203]. KIFAP3
forms a trimeric kinesin motor complex (KIF3) with KIF3A
and KIF3B. The KIF3-complex is abundantly expressed in
neuronal tissue and is known to function as motor for
anterograde transport of membrane-bound organelles and
neurite extension. The role of KIFAP3 is thought to mediate
the binding to cargo. Interestingly, KIFAP3 has been shown
to associate with misfolded SOD1 species and incorporates
into SOD1 aggregates of FALS patients [206]. In SOD1
G86R mice, KIFAP3 is up-regulated during the asymptomatic phase in the lumbar spinal cord, long before
axonal degeneration. The KIFAP3 protein also accumulates in large motor neurons of the ventral spinal cord [60].
Down-regulation of other kinesins has also been detected
in SALS [155].
RNA processing is also implicated with the proganulin
gene (PGRN). Over 50 mutations in PGRN have been
identified in patients with FTLD who have tau-negative,
282
Conclusions
The recent identification of two RNA binding proteins,
TDP-43 and FUS/TLS, that when mutated cause ALS has
lead researchers to further evaluate the RNA processing
pathway as a common pathogenic pathway. Within this
review, we have focused on six RNA processing genes
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