An acetylation switch controls TDP-43 function and aggregation propensity.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• TDP-43 pathology is a key feature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP).
• The precise regulation of TDP-43's function as an RNA-binding protein remains incompletely understood.

Purpose of the Study:

• To identify novel post-translational modifications regulating TDP-43 function.
• To investigate the role of lysine acetylation in controlling TDP-43 aggregation and pathogenicity.

Main Methods:

• Biochemical assays to assess TDP-43 acetylation and RNA binding.
• Cell-based models to study TDP-43 aggregation under oxidative stress.
• Analysis of patient samples for pathological TDP-43 acetylation.

Main Results:

• Lysine acetylation was identified as a novel post-translational modification of TDP-43.
• Acetylated TDP-43 exhibits impaired RNA binding and promotes the formation of insoluble, hyper-phosphorylated species.
• Oxidative stress induces acetylated TDP-43 aggregates, which are recognized by cellular defense mechanisms.
• Pathological TDP-43 acetylation was detected in ALS patient spinal cords.

Conclusions:

• Aberrant TDP-43 acetylation contributes to TDP-43 proteinopathies by impairing RNA binding and promoting aggregation.
• Modulating TDP-43 acetylation presents a potential therapeutic strategy for ALS and FTLD-TDP.