Abstract
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.
Highlights
Amyotrophic lateral sclerosis, the most common form of motor neuron disease, is characterized by the progressive loss of upper and lower motor neurons, leading to death2–4 years post-diagnosis, usually due to respiratory failure [1]
Maurel et al (2020) identified a unique consensus site for SUMOylation at lysine-136 of TAR DNA-binding protein 43 (TDP-43) [69]. They further show that replacement of this residue with an arginine altered the intracellular localization of TDP-43 aggregates from the cytoplasm to the nucleus, indicating that SUMOylation of this residue is critical to TDP-43 cytoplasmic localization [69]
Camta1 and Dennd4a are associated with neurodegeneration, TDP-43 regulation of these transcripts may be involved in Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)
Summary
Amyotrophic lateral sclerosis, the most common form of motor neuron disease, is characterized by the progressive loss of upper and lower motor neurons, leading to death. 12.5% of FTLD cases have concomitant motor neuron disease, with a further 30% showing signs of motor neuron dysfunction [3]. Mutations in TARDBP, coding for mutant TDP-43 proteins, are a rare cause of ALS and FTLD [12]. The TDP-43 observed in degenerating neurons in ALS and FTLD tissues in both mutation and non-mutation cases is abnormally cytoplasmic, hyperphosphorylated, ubiquitinated and often cleaved, giving rise to C-terminal fragments (CTFs) [16,17,18]. TDP-43 is primarily a nuclear protein, the cytoplasmic mislocalization and aggregation of TDP-43 are considered important pathogenic mechanisms in ALS and FTLD. While the exact contribution of TDP-43 cytoplasmic mislocalization and aggregation to disease progression is unclear, both loss and gain of function are thought to be involved. We will summarize and discuss the molecular mechanisms that have been identified in cellular and animal models of TDP-43 proteinopathies
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