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SUMMARY:FUS overexpression leads to cytoskeletal\, organelle and cellular 
 homeostasis perturbations - Prof Gabriele Kaminski Schierle\; University o
 f Cambridge
DTSTART:20220906T120000Z
DTEND:20220906T130000Z
UID:TALK176477@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:Aberrant formation of fused-in sarcoma (FUS) protein condensat
 es in the cytoplasm is implicated in the pathology of amyotrophic lateral 
 sclerosis and frontotemporal lobal degeneration. The molecular mechanisms 
 that connect the formation of such condensates to biological malfunction a
 re incompletely understood. Here\, we develop an approach to determine the
  viscosity of condensates in live mammalian cells and find that disease-re
 lated mutants of FUS form more viscous condensates when compared to wild-t
 ype (WT-)FUS\, with ALS-associated P525L-FUS forming the most viscous cond
 ensates. Moreover\, P525L-FUS causes severe changes in the mechanoproperti
 es of cells by affecting the levels of actin and tubulin polymerisation\, 
 both of which have an impact on cytoskeletal stiffness\, and increases euc
 hromatin formation. We further show that some of the main cellular organel
 les\, such as lysosomes\, mitochondria\, and the tubular endoplasmic retic
 ulum (ER) network\, are significantly impaired in the presence of FUS. The
 se might be related to defects in the tubulin network\, as the latter faci
 litates organelle transport but also their formation\, fission and fusion.
  We also observe significant increases in the biogenesis\, size and pH of 
 lysosomes\, suggesting that autophagy pathways may be upregulated. Over-ex
 pression of FUS in cells significantly increases the cytoplasmic-to-nuclea
 r of the transcription factor EB (TFEB)\, i.e.\, the master gene for induc
 ing autophagy. Despite TFEB translocation and subsequent increased lysosom
 al biogenesis\, however\, increased autophagy needed for protein aggregate
  clearance is not observed to occur. Our study reveals that the formation 
 of highly viscous FUS condensates significantly impacts cytoskeletal/organ
 elle function and cellular homeostasis. The latter are closely associated 
 with cell ageing\, hence poses the question whether mutant FUS induces ear
 ly cellular senescence.\n\nGabriele Kaminski Schierle is Professor of Mole
 cular Neuroscience at the University of Cambridge\, UK\, where she leads t
 he Molecular Neuroscience group (https://www.ceb-mng.org/). Her group has 
 pioneered optical techniques for the study of the molecular causes underly
 ing neurodegenerative diseases\, such as Alzheimer’s and Parkinson’s. 
 She is the director of MPhil in Biotechnology at the department of Chemica
 l Engineering and Biotechnology and senior fellow at the higher education 
 academy.\n\nClick here to join live - https://us06web.zoom.us/j/8230570478
 1 
LOCATION:Online via zoom &amp\; Queen Edith Room
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