Details

Autor(en) / Beteiligte

• Klim, Joseph R.
• Pintacuda, Greta
• Nash, Leslie A.
• Guerra San Juan, Irune
• Eggan, Kevin

Titel

Connecting TDP-43 Pathology with Neuropathy

Ist Teil von

• Trends in neurosciences (Regular ed.), 2021-06, Vol.44 (6), p.424-440

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. The list of diseases associated with TDP-43 aggregation has grown beyond ALS and FTD.Genetic findings implicate impaired proteostasis in disease pathogenesis, and molecular studies tie decreased protein turnover to TDP-43 aggregation.Mutations in the glycine-rich domain of TDP-43 incriminate altered phase separation in disease pathogenesis, and new mutations in the RNA recognition motifs potentially affect both RNA binding and solubility.Altered regulation of critical neuronal transcripts, including STMN2, is associated with the loss of TDP-43 function, providing a mechanistic link between TDP-43 and neuropathy.Aberrant changes in STMN2 expression in other neurodegenerative diseases spotlight the critical nature of this cytoskeletal regulator.Key TDP-43-regulated transcripts may serve as biomarkers for detecting, characterizing, and treating associated proteinopathies.