FIGURE 2.

TDP-43 mutations and proteinopathy disrupt multiple biological processes in ALS. While this is depicted in a neuron, effects in glia and other cell types should not be ruled out, but are not included due to a lack of comparable data. (A) The pre-mRNA splicing function of TDP-43, one of its well-characterized roles in the RNA metabolism, is compromised in ALS neurons leading to altered alternative splicing as well as insertion of abnormal sequences via splicing of non-coding cryptic exons and downstream widespread los-of-function effects through mRNA instability and potential translation of abnormal/misfolded proteins. (B) Mis-localization of proteins such as TDP-43 and FUS from the neuronal nucleus is a major pathological event in ALS. Mis-localized proteins undergo aberrant phase separations, alter stress granule dynamics and develop into insoluble aggregates in the cytoplasm. In some ALS proteinopathies, mis-localized proteins enter neuronal mitochondria, forming pre-inclusions or fully insoluble aggregates, altering mitochondria morphology, dynamics and function. (C) Normal mitochondrial function is undermined as pathogenic forms of TDP-43 process mtDNA derived transcripts, resulting in down regulation or misfolding of essential mitochondrial proteins, including those related to the electron transport chain/oxidative phosphorylation, and disrupting mitochondrial homeostasis. (D) ALS proteinopathies have been associated with de-stabilization or disassembly of complex I of the electron transport chain, or through interactions with ATP5B thereby reducing ATP production. (E) Protein degradation systems become overwhelmed as misfolded proteins and insoluble aggregates accumulate in neurons and glia, while TDP-43 is depleted and ATP supply is compromised. (F) Mitochondrial function failing leads to reduced Ca^{2 +} buffering capacity, with an excess of cytoplasmic Ca^{2 +} and an increase in the production of reactive oxygen species triggering excitotoxic damage which will eventually result in mitochondrial breakdown and neuronal degeneration.Created with BioRender.com.