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Fig. 11 | Molecular Neurodegeneration

Fig. 11

From: Impaired NHEJ repair in amyotrophic lateral sclerosis is associated with TDP-43 mutations

Fig. 11

Hypothetical model illustrating the relationship between DNA damage and neurodegeneration in ALS. TDP-43 normally functions in NHEJ to repair cytotoxic DSBs, the only DNA DSB repair mechanism available in post-mitotic neurons. However, in familial ALS, misfolded mutant TDP-43 lacks this function, leading to DNA damage and neurodegeneration. Similarly, other mutant proteins associated with ALS also induce DNA damage. In sporadic ALS, oxidative stress or other forms of cellular stress induce DNA damage. In all cases, this results in TDP-43 mis-localisation to the cytoplasm, loss of nuclear TDP-43 and impairment of NHEJ. The resulting DNA damage induces further TDP-43 mis-localization to cytoplasm and more perturbation of DNA repair in the nucleus, creating a viscous cycle which exacerbates nuclear DNA damage, inducing TDP-43 pathology, and leading to genomic instability and eventually neurodegeneration

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