TDP-43 Depletion: Mechanism of Neuronal Cell Death in ALS

Abstract

Trans activation response DNA/RNA-binding protein 43 kDa (TDP-43) regulates RNA splicing and stability. TDP-43 is a component of ubiquitin-positive inclusion bodies of motor neurons from patients with amyotrophic lateral sclerosis, suggesting a role in disease pathogenesis. Toxic intracellular TDP-43 aggregation may cause neuronal cell death. The loss of TDP-43 in animal models causes lethality in early development. Furthermore, TDP-43 knockdown in adult animals and cells increases aberrant splicing. Uridine-rich small nuclear RNA (U snRNA) regulation is disrupted in cultured neuroblastoma cells with TDP-43 knockdown and in motor neurons in amyotrophic lateral sclerosis. Aberrant mRNA splicing and U snRNA expression are likely key processes in neuronal cell death. We review the research history and future perspectives of aberrant splicing by TDP-43 loss.

Keywords::

• neuronal cell death
• protein aggregates
• RNA splicing
• transactivation response DNA/RNA-binding protein 43 kDa
• U snRNAs

Financial & competing interests disclosure

A Kitamura was supported by a Japan Society for Promotion of Science (JSPS) Grant-in-Aid for the Promotion of Joint International Research (Fostering Joint International Research) (16KK0156) and a JSPS Grand-in-Aid for Scientific Research (C) (18K06201). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

A Kitamura was supported by a Japan Society for Promotion of Science (JSPS) Grant-in-Aid for the Promotion of Joint International Research (Fostering Joint International Research) (16KK0156) and a JSPS Grand-in-Aid for Scientific Research (C) (18K06201). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.