Mutations in TDP-43 in ALS
There are a large number of known (at least 60) mutations in this gene
which have been identified in ALS. Certain mutations in this gene are
responsible for the development of several other neurodegenerative
disorders, including primary lateral sclerosis, progressive muscular
atrophy and frontotemporal dementia (FTD), a disease that affects
personality, behavior, and language. Yet, TDP-43 mutations only account
for an estimated 5-10 % of familial ALS (fALS) patients \cite{Prasad_2019}(Prasad et al.,
2019), while the remainder of fALS mutations occur in other ALS-linked
genes, the most well-characterized of which are the superoxide dismutase
(SOD1) , chromosome 9 open reading frame 72 (C9ORF72) , and
fused in sarcoma (FUS) genes. fALS-associated genes, all of which
are inherited in a autosomal dominant fashion. However, TDP-43 remains a
promising therapeutic target even when a patient does not have a
mutation evident in the TARDBP gene, given that the majority
(95%) of ALS patients (sporatic and familial), exhibit TDP-43 neuronal
inclusions in their cortical and spinal cord neurons. TDP-43 was found
to be a major constituent of ubiquitin-positive inclusions in ALS
patients\cite{Arai_2006}. Leading to the recognition of this
protein aggregate as a hallmark of ALS\cite{Wolozin_2019}. In addition, in
ALS there is a perturbation in TDP-43 trafficking between the cytoplasm
and nucleus. The TDP-43 protein is predominantly localized to the
nucleus under normal endogenous conditions. However, sequestration of
the protein in the cytoplasm, results in loss of endogenous TDP-43
function and to accumulation of insoluble cytoplasmic aggregates.
Evidence suggests that the N-terminal domain (NTD) of TDP-43 proteins, a
region which contains its nuclear localization signal, homodimerizes
with its protein partners and appears important in its function of
targeting splicing of RNA. In fact, mutation of the nuclear localization
or nuclear export signals results in cytoplasmic or nuclear aggregate
formation\cite{Winton_2008}, whereas exogenous accumulation of
cytoplasmic TDP-43 has been demonstrated to be specifically cytotoxic in
primary rat cortical neurons. Therefore, homeostatic auto-regulation of
TDP-43 is critical for its normal function. Normally, TDP-43 binds to
the 3’ UTR of its own pre-mRNA, which leads to its undergoing of
nonsense-mediated mRNA decay\cite{Ayala_2010}, thereby decreasing the
nuclear to cytoplasmic shuttling of the transcript as well as its
corresponding translation in the functional protein\cite{Koyama_2016}. Loss of homeostasic nucleo-cytoplasmic localization resulting in
either nuclear or cytoplasmic TDP-43 aggregates appears critical is the
pathology of all variants of ALS. Pathogenic TDP-43 inclusion bodies,
becomes cleaved at the C-terminus, ubiquitinated and hyperphyphorylated,
and targeted for autophagosomal removal . (Chang et al., 2016)
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