[Neurodegenerative disorders and TDP-43]

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Context:

• Neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by intracellular protein aggregates.
• TAR DNA-binding protein of 43 KDa (TDP-43) is a major component of these inclusions, defining TDP-43 proteinopathies.
• Posttranslational modifications, such as phosphorylation and ubiquitination, are observed on TDP-43 in affected brains.

Purpose:

• To investigate the role of TDP-43 posttranslational modifications in the formation of protein aggregates.
• To develop specific antibodies for detecting abnormally phosphorylated TDP-43.
• To identify protein kinases responsible for aberrant TDP-43 phosphorylation.

Summary:

• Polyclonal and monoclonal antibodies specific for phosphorylated TDP-43 (pTDP-43) at Ser409/Ser410 were generated and validated.
• Immunohistochemical and immunoblot analyses confirmed the presence of phosphorylated and fragmented TDP-43 in FTLD and ALS brains.
• Casein kinase 1 was identified as a candidate kinase mediating abnormal TDP-43 phosphorylation.
• In vitro studies demonstrated that phosphorylated TDP-43 exhibits increased fibrillation propensity compared to wild-type TDP-43.

Impact:

• This research provides novel tools (specific antibodies) for studying TDP-43 proteinopathies.
• Identification of casein kinase 1 offers a potential therapeutic target for modulating TDP-43 aggregation.
• Understanding TDP-43 phosphorylation and aggregation mechanisms offers insights into neurodegenerative disease pathogenesis.
• The findings contribute to the broader understanding of TDP-43's role in FTLD and ALS.