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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