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Molecular mechanisms underlying TDP-43 pathology in cellular and animal models of ALS and FTLD

Wood, A., Gurfinkel, Y., Polain, N., Lamont, W. and Rea, S.L. (2021) Molecular mechanisms underlying TDP-43 pathology in cellular and animal models of ALS and FTLD. International Journal of Molecular Sciences, 22 (9). Article 4705.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: MDPI AG
Copyright: © 2021 The Authors
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