Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models
Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models
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DOI：
10.15252/embr.201745409
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发表时间：
2018-09-01
期刊：
影响因子：
7.7
通讯作者：
Chan, Ho Yin Edwin
中科院分区：
文献类型：
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作者：
Chen, Zhefan Stephen;Li, Li;Chan, Ho Yin Edwin
平面细胞极性（PCP）描述了细胞与细胞之间的通讯过程，通过该过程，各个细胞在组织平面内进行协调和排列。在这项研究中，我们发现 PCP 基因 Fuz 的过度表达通过不规则/Rac1 GTPase/MEKK1/JNK/caspase 信号轴触发神经元凋亡。与这一发现一致的是，内源性 Fuz 表达在多聚谷氨酰胺 (polyQ) 疾病模型和脊髓小脑共济失调 3 型 (SCA3) 患者的成纤维细胞中上调。这种上调的破坏可以减轻聚 Q 诱导的果蝇神经变性。我们发现转录调节因子 Yin Yang 1 (YY1) 与 Fuz 启动子相关。 YY1 的过度表达会促进 Fuz 启动子的高甲基化，从而导致 Fuz 的转录抑制。值得注意的是，YY1 蛋白被招募到 ATXN3-Q84 聚集体中，从而降低功能性可溶性 YY1 的水平，导致 Fuz 转录去阻遏并诱导神经元凋亡。此外，Fuz 转录水平在淀粉样蛋白 β 肽、Tau 和 α-突触核蛋白模型中升高，表明其可能参与其他神经退行性疾病，如阿尔茨海默病和帕金森病。总而言之，这项研究揭示了神经退行性疾病中一种通用的 Fuz 介导的细胞凋亡途径。
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.