Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models
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AbstractPlanar cell polarity (PCP) describes a cell-cell communication process through which individual cells coordinate and align within the plane of a tissue. In this study, we show that overexpression of Fuz, a PCP gene, triggers neuronal apoptosis via the dishevelled/Rac1 GTPase/MEKK1/JNK/caspase signalling axis. Consistent with this finding, endogenous Fuz expression is upregulated in models of polyglutamine (polyQ) diseases and in fibroblasts from spinocerebellar ataxia type 3 (SCA3) patients. The disruption of this upregulation mitigates polyQ-induced neurodegeneration in Drosophila We show that the transcriptional regulator Yin Yang 1 (YY1) associates with the Fuz promoter. Overexpression of YY1 promotes the hypermethylation of Fuz promoter, causing transcriptional repression of Fuz Remarkably, YY1 protein is recruited to ATXN3-Q84 aggregates, which reduces the level of functional, soluble YY1, resulting in Fuz transcriptional derepression and induction of neuronal apoptosis. Furthermore, Fuz transcript level is elevated in amyloid beta-peptide, Tau and α-synuclein models, implicating its potential involvement in other neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Taken together, this study unveils a generic Fuz-mediated apoptotic cell death pathway in neurodegenerative disorders.
All Author(s) ListChen ZS, Li L, Peng S, Chen FM, Zhang Q, An Y, Lin X, Li W, Koon AC, Chan TF, Lau KF, Ngo JCK, Wong WT, Kwan KM, Chan HYE.
Journal nameEMBO Reports
Volume Number19
Issue Number9
PublisherEMBO Press
Article numbere45409
LanguagesEnglish-United Kingdom
KeywordsTau, Yin Yang 1, alpha‐synuclein, amyloid beta‐peptide, polyglutamine

Last updated on 2021-14-10 at 23:45