Connecting TDP-43 Pathology with Neuropathy

Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.

Automated summary

TDP-43 is a multifunctional nucleic acid-binding protein associated with several devastating nervous system disorders. Dysfunction of TDP-43 leads to RNA homeostasis disruption and neural degeneration. Recent findings connecting TDP-43 dysfunction with improper splicing of STMN2 highlight a potential mechanistic link between TDP-43 proteinopathies and neuropathy.