Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington’s disease

• DOI: 10.1016/j.celrep.2023.112198
• Publication Date: 2023-03-03T00:30:58Z
• Authors: Rachel H. Mansky; Erin A. Greguske; Dahyun Yu; Nicole Zarate; Taylor A. Intihar; Wei Tsai; Taylor G. Brown; Mackenzie N. Thayer; Kompal Kumar; Rocio Gomez-Pastor
• Keywords: HSF1

p53 and HSF1 are two major transcription factors involved in cell proliferation apoptosis, whose dysregulation contributes to cancer neurodegeneration. Contrary most cancers, is increased Huntington's disease (HD) other neurodegenerative diseases, while decreased. reciprocal regulation has been shown different contexts, but their connection neurodegeneration remains understudied. Using cellular animal models of HD, we show that mutant HTT stabilized by abrogating the interaction between E3 ligase MDM2. Stabilized promotes protein kinase CK2 alpha prime FBXW7 transcription, both which responsible for degradation. Consequently, deletion striatal neurons zQ175 HD mice restores abundance decrease aggregation pathology. Our work shows mechanism connecting stabilization with degradation pathophysiology sheds light on broader molecular differences commonalities