Structures of pathological TDP-43 filaments in human neurodegenerative disease

Host: Prof Liz Miller

Venue: MSI, Small Lecture, SLS

Abstract:

 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. 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