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CATEGORIES:Babraham Seminar
SUMMARY:FUS overexpression leads to cytoskeletal\, organel
 le and cellular homeostasis perturbations - Prof G
 abriele Kaminski Schierle\; University of Cambridg
 e
DTSTART;TZID=Europe/London:20220906T130000
DTEND;TZID=Europe/London:20220906T140000
UID:TALK176477AThttp://talks.cam.ac.uk
URL:http://talks.cam.ac.uk/talk/index/176477
DESCRIPTION:Aberrant formation of fused-in sarcoma (FUS) prote
 in condensates in the cytoplasm is implicated in t
 he pathology of amyotrophic lateral sclerosis and 
 frontotemporal lobal degeneration. The molecular m
 echanisms that connect the formation of such conde
 nsates to biological malfunction are incompletely 
 understood. Here\, we develop an approach to deter
 mine the viscosity of condensates in live mammalia
 n cells and find that disease-related mutants of F
 US form more viscous condensates when compared to 
 wild-type (WT-)FUS\, with ALS-associated P525L-FUS
  forming the most viscous condensates. Moreover\, 
 P525L-FUS causes severe changes in the mechanoprop
 erties of cells by affecting the levels of actin a
 nd tubulin polymerisation\, both of which have an 
 impact on cytoskeletal stiffness\, and increases e
 uchromatin formation. We further show that some of
  the main cellular organelles\, such as lysosomes\
 , mitochondria\, and the tubular endoplasmic retic
 ulum (ER) network\, are significantly impaired in 
 the presence of FUS. These might be related to def
 ects in the tubulin network\, as the latter facili
 tates organelle transport but also their formation
 \, fission and fusion. We also observe significant
  increases in the biogenesis\, size and pH of lyso
 somes\, suggesting that autophagy pathways may be 
 upregulated. Over-expression of FUS in cells signi
 ficantly increases the cytoplasmic-to-nuclear of t
 he transcription factor EB (TFEB)\, i.e.\, the mas
 ter gene for inducing autophagy. Despite TFEB tran
 slocation and subsequent increased lysosomal bioge
 nesis\, however\, increased autophagy needed for p
 rotein aggregate clearance is not observed to occu
 r. Our study reveals that the formation of highly 
 viscous FUS condensates significantly impacts cyto
 skeletal/organelle function and cellular homeostas
 is. The latter are closely associated with cell ag
 eing\, hence poses the question whether mutant FUS
  induces early cellular senescence.\n\nGabriele Ka
 minski Schierle is Professor of Molecular Neurosci
 ence at the University of Cambridge\, UK\, where s
 he leads the Molecular Neuroscience group (https:/
 /www.ceb-mng.org/). Her group has pioneered optica
 l techniques for the study of the molecular causes
  underlying neurodegenerative diseases\, such as A
 lzheimer’s and Parkinson’s. She is the director of
  MPhil in Biotechnology at the department of Chemi
 cal Engineering and Biotechnology and senior fello
 w at the higher education academy.\n\nClick here t
 o join live - https://us06web.zoom.us/j/8230570478
 1 
LOCATION:Online via zoom &amp\; Queen Edith Room
CONTACT:Bobbie Claxton
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