Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program

Area of Science:

• Neurobiology
• Molecular Biology
• Proteinopathies

Background:

• TDP-43 pathology is central to multisystem proteinopathies, including ALS and FTLD.
• Current understanding of TDP-43 regulatory mechanisms is incomplete, hindering disease modeling.
• Replicating TDP-43 pathology in experimental systems has proven challenging.

Purpose of the Study:

• To investigate the role of TDP-43 acetylation in initiating disease pathology.
• To elucidate the molecular mechanisms underlying TDP-43 aggregation and cellular response.
• To identify potential therapeutic strategies for TDP-43 proteinopathies.

Main Methods:

• Utilized cultured cells and mouse skeletal muscle models.
• Employed acetylation-mimic constructs to study TDP-43 modification.
• Analyzed protein-protein interactions and cellular responses, including mitochondrial function and inflammation.
• Investigated the role of HSF1 in TDP-43 disaggregation.

Main Results:

• TDP-43 acetylation mimics promoted TDP-43 phosphorylation and ubiquitination.
• Acetylation-mimic pathology induced mitochondrial dysfunction and inflammatory responses.
• Key ALS proteins (p62, ubiquilin-2, optineurin) were recruited to TDP-43 aggregates.
• HSF1-dependent mechanisms potently suppressed TDP-43 acetylation-mimic pathology by promoting disaggregation.

Conclusions:

• TDP-43 acetylation acts as a trigger for disease pathology.
• A coordinated chaperone response, involving HSF1, targets TDP-43 aggregation.
• Restoring refolding mechanisms may alleviate TDP-43 aggregation in susceptible tissues.