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SUMMARY:Special LMNN Seminar- RNA-binding proteins in neurodegeneration 
 – from nuclear transport defects to aberrant phase transitions
DTSTART:20181122T090000
DTEND:20181122T100000
DTSTAMP:20260506T084455Z
UID:906b774fef5ac8b660c785a07ea12fbbbe38ed826b0c84cda32ec485
CATEGORIES:Conferences - Seminars
DESCRIPTION:Dorothee Dormann\, BioMedizinisches Centrum (BMC) Ludwig-Maxim
 ilians-Universität München - LMU\, Germany\nPathological protein aggreg
 ates are a central hallmark of all neurodegenerative diseases. In the rela
 ted disorders ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal 
 dementia)\, the pathological aggregates consist mostly of the ubiquitous R
 NA-binding proteins TDP-43 or FUS. Both proteins are usually located in th
 e nucleus\, whereas in neurons and glial cells of ALS/FTD patients\, they 
 are partially lost from the nucleus and accumulate in large cytoplasmic in
 clusions. Which molecular defects cause TDP-43 or FUS mislocalization and 
 aggregation in ALS/FTD patients and how we can possibly prevent or revert 
 them are central questions that we try to address in my lab.\nFor FUS\, we
  have successfully used cellular and in vitro models combined with neuropa
 thological analysis of human post-mortem brains to identify key pathomecha
 nisms that cause FUS mislocalization and aggregation in ALS and FTD patien
 ts: In ALS-FUS\, genetic mutations in the nuclear localization signal (NLS
 ) of FUS cause impaired binding to the nuclear import receptor Transportin
 . This defect impairs nuclear import of FUS and\, upon cellular stress\, f
 avors recruitment of FUS into stress granules\, where FUS aggregation may 
 be promoted due to high local FUS concentrations. In FTD-FUS patients\, Tr
 ansportin is aggregated and a post-translational modification of FUS\, arg
 inine methylation\, is lost. Recently\, we have shown that both Transporti
 n and arginine methylation keep FUS soluble in the cytoplasm and prevent a
 berrant liquid-to-solid state transition and accumulation of FUS in stress
  granules. Our work suggests that certain binding proteins and post-transl
 ational modifications can modulate aberrant solidification of ALS/FTD-link
 ed RNA-binding proteins and hence could potentially be targeted in new the
 rapeutic approaches.
LOCATION:AI 1153 https://plan.epfl.ch/?room==AI%201153
STATUS:CONFIRMED
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