Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0002736 (
amyotrophic lateral sclerosis
)
19,048
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
FUS and EWSR1 are RNA-binding proteins with prion-like domains (PrLDs) that aggregate in
amyotrophic lateral sclerosis
(
ALS
) and frontotemporal dementia (FTD). The
FUS
and
EWSR1
genes are also prone to chromosomal translocation events, which result in aberrant fusions between portions of the PrLDs of FUS and EWSR1 and the transcription factors CHOP and FLI. The resulting fusion proteins,
FUS-CHOP
and EWS-FLI, drive aberrant transcriptional programs that underpin liposarcoma and Ewing's sarcoma, respectively. The translocated PrLDs alter the expression profiles of these proteins and promote their phase separation and aggregation. Here, we report the development of yeast models of
FUS-CHOP
and EWS-FLI toxicity and aggregation. These models recapitulated several salient features of sarcoma patient cells harboring the
FUS-CHOP
and EWS-FLI translocations. To reverse FUS and EWSR1 aggregation, we have explored Hsp104, a hexameric AAA+ protein disaggregase from yeast. Previously, we engineered potentiated Hsp104 variants to suppress the proteotoxicity, aggregation, and mislocalization of FUS and other proteins that aggregate in
ALS
/FTD and Parkinson's disease. Potentiated Hsp104 variants that robustly suppressed FUS toxicity and aggregation also suppressed the toxicity and aggregation of
FUS-CHOP
and EWS-FLI. We suggest that these new yeast models are powerful platforms for screening for modulators of
FUS-CHOP
and EWS-FLI phase separation. Moreover, Hsp104 variants might be employed to combat the toxicity and phase separation of aberrant fusion proteins involved in sarcoma.
...
PMID:Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma. 3173 85
