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SUMMARY:Structures of pathological TDP-43 filaments in human neurodegenera
 tive disease - Diana Arseni ( MRC-Laboratory of Molecular Biology)
DTSTART:20250123T160000Z
DTEND:20250123T170000Z
UID:TALK227116@talks.cam.ac.uk
CONTACT:Michael Boemo
DESCRIPTION:Abnormal assemblies of TDP-43 in neurons and glia are the path
 ological hallmark of amyotrophic lateral sclerosis (ALS) and multiple type
 s of frontotemporal lobar degeneration (FTLD). Mutations in the TDP-43 gen
 e\, TARDBP\, can cause ALS and FTLD\, and the temporospatial accumulation 
 of TDP-43 assemblies correlates with neurodegeneration\, indicating a caus
 ative role for TDP-43 assembly in disease. TDP-43 assemblies are also comm
 on co-pathologies in other diseases\, including Alzheimer's\, Parkinson's 
 and Huntington's. The structural and molecular mechanisms of TDP-43 assemb
 ly in disease are poorly understood. We developed a protocol to isolate as
 sembled TDP-43 from the brains of patients with ALS and FTLD and determine
 d their structures using cryo-electron microscopy (cryo-EM). We found that
  TDP-43 assembles into amyloid filaments in these diseases. The ordered fi
 lament cores are comprised of the first half of the TDP-43 low-complexity 
 domain and adopt distinct filament folds in different neurodegenerative co
 nditions. 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 mod
 ifications of assembled TDP-43\, citrullination and mono-methylation of R2
 93\, and suggest that they may facilitate filament formation and observed 
 structural variation within individual filaments. Unexpectedly\, the struc
 tures also revealed that in specific cases TDP-43 can also co-assemble wit
 h Annexin A11 in heteromeric amyloid filaments. The structures of TDP-43 a
 myloid filaments from ALS and FTLD guide mechanistic studies of TDP-43 ass
 embly\, as well as the development of diagnostic and therapeutic compounds
  for TDP-43 proteinopathies
LOCATION:Lecture Theatre\, Department of Pathology\, Tennis Court Road
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