Journal
EMBO REPORTS
Volume 19, Issue 9, Pages -Publisher
WILEY
DOI: 10.15252/embr.201745409
Keywords
alpha-synuclein; amyloid beta-peptide; polyglutamine; Tau; Yin Yang 1
Categories
Funding
- Hong Kong Research Grants Council [14100714]
- CUHK Vice-Chancellor's One-Off Discretionary Fund [VCF2014011]
- CUHK One-off Funding for Joint Lab/Research Collaboration [3132980]
- CUHK Faculty of Science Strategic Development Fund [FACULTY-P17173]
- CUHK Gerald Choa Neuroscience Centre [7105306]
- Chow Tai Fook Charity Foundation [6903898]
- Hong Kong Spinocerebellar Ataxia Association [6903291]
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Planar 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 alpha-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.
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