Structures of pathological TDP-43 filaments in human neurodegenerative disease

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• Diana Arseni ( MRC-Laboratory of Molecular Biology)
• Thursday 23 January 2025, 16:00-17:00
• Lecture Theatre, Department of Pathology, Tennis Court Road.

If you have a question about this talk, please contact Michael Boemo.

Abnormal assemblies of TDP -43 in neurons and glia are the pathological hallmark of amyotrophic lateral sclerosis (ALS) and multiple types of frontotemporal lobar degeneration (FTLD). Mutations in the TDP -43 gene, TARDBP , can cause ALS and FTLD , and the temporospatial accumulation of TDP -43 assemblies correlates with neurodegeneration, indicating a causative role for TDP -43 assembly in disease. TDP -43 assemblies are also common co-pathologies in other diseases, including Alzheimer’s, Parkinson’s and Huntington’s. The structural and molecular mechanisms of TDP -43 assembly in disease are poorly understood. We developed a protocol to isolate assembled TDP -43 from the brains of patients with ALS and FTLD and determined their structures using cryo-electron microscopy (cryo-EM). We found that TDP -43 assembles into amyloid filaments in these diseases. The ordered filament cores are comprised of the first half of the TDP -43 low-complexity domain and adopt distinct filament folds in different neurodegenerative conditions. These brain-derived filament folds show no similarity to TDP -43 filament folds formed in vitro. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP -43, citrullination and mono-methylation of R293 , and suggest that they may facilitate filament formation and observed structural variation within individual filaments. Unexpectedly, the structures also revealed that in specific cases TDP -43 can also co-assemble with Annexin A11 in heteromeric amyloid filaments. The structures of TDP -43 amyloid filaments from ALS and FTLD guide mechanistic studies of TDP -43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP -43 proteinopathies

This talk is part of the Computational and Systems Biology Seminar Series series.

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• Lecture Theatre, Department of Pathology, Tennis Court Road

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