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SUMMARY:Mutant HTT aggregation and conformers: what we know and what we do
 n’t know - Erich E. Wanker\, Head Neuroproteomics and Molecular Mechanis
 ms of Neurodegenerative Diseases\, Max Delbrueck Center for Molecular Medi
 cine (MDC) Berlin-Buch
DTSTART:20170621T093000Z
DTEND:20170621T103000Z
UID:TALK73134@talks.cam.ac.uk
CONTACT:Priyanka Joshi
DESCRIPTION:Self-propagation of amyloidogenic protein aggregates may drive
  the progression of neurodegenerative diseases including Huntington’s di
 sease (HD). We recently developed of a cell-free\, FRET-based mutant hunti
 ngtin (mHTT) aggregate seeding (FRASE) biosensor assay that enables the de
 tection and quantification of mHTT seeding activity (HSA) in complex biosa
 mples from HD patients and disease models. Application of FRASE assays rev
 ealed HSA in crude brain homogenates of presymptomatic HD transgenic mice 
 and its progressive increase with development of the phenotype\, indicatin
 g that HSA quantitatively tracks disease progression. Biochemical investig
 ations of mouse brain homogenates demonstrated that HSA is predominantly d
 etectable in soluble protein fractions\, which contain small\, fibrillar m
 HTT oligomers. Finally\, we assessed the disease relevance of mHTT exon-1 
 (mHTTex1) seeds in an inducible Drosophila fly model. We demonstrated that
  the short-time production of seeding-competent mHTTex1 aggregates in fly 
 brains leads to a dramatically reduced lifespan\, suggesting that mutant H
 TTex1 seeds are highly toxic structures. Together\, our results suggest a 
 central role of self-propagating mHTT seeds in the development and progres
 sion of HD. \n
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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