Raj Kritika, Sarkar Surajit
Department of Genetics, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India.
J Mol Neurosci. 2017 May;62(1):55-66. doi: 10.1007/s12031-017-0910-4. Epub 2017 Mar 18.
Polyglutamine (poly(Q)) disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, represent a group of neurological disorders which arise due to an atypically expanded poly(Q) tract in the coding region of the affected gene. Pathogenesis of these disorders inside the cells begins with the assembly of these mutant proteins in the form of insoluble inclusion bodies (IBs), which progressively sequester several vital cellular transcription factors and other essential proteins, and finally leads to neuronal dysfunction and apoptosis. We have shown earlier that targeted upregulation of Drosophila myc (dmyc) dominantly suppresses the poly(Q) toxicity in Drosophila. The present study examines the ability of the human c-myc proto-oncogene and also identifies the specific c-Myc isoform which drives the mitigation of poly(Q)-mediated neurotoxicity, so that it could be further substantiated as a potential drug target. We report for the first time that similar to dmyc, tissue-specific induced expression of human c-myc also suppresses poly(Q)-mediated neurotoxicity by an analogous mechanism. Among the three isoforms of c-Myc, the rescue potential was maximally manifested by the full-length c-Myc2 protein, followed by c-Myc1, but not by c-MycS which lacks the transactivation domain. Our study suggests that strategies focussing on the transactivation domain of c-Myc could be a very useful approach to design novel drug molecules against poly(Q) disorders.
多聚谷氨酰胺（poly(Q)）疾病，如亨廷顿舞蹈症（HD）和脊髓小脑共济失调，是一类神经疾病，由受影响基因编码区异常扩展的多聚谷氨酰胺序列引起。这些疾病在细胞内的发病机制始于这些突变蛋白以不溶性包涵体（IBs）的形式聚集，逐渐隔离多种重要的细胞转录因子和其他必需蛋白，最终导致神经元功能障碍和细胞凋亡。我们之前已表明，果蝇myc（dmyc）的靶向上调可显著抑制果蝇中的多聚谷氨酰胺毒性。本研究检测了人类c-myc原癌基因的能力，并确定了驱动减轻多聚谷氨酰胺介导的神经毒性的特定c-Myc亚型，以便其可作为潜在药物靶点得到进一步证实。我们首次报道，与dmyc类似，人类c-myc的组织特异性诱导表达也通过类似机制抑制多聚谷氨酰胺介导的神经毒性。在c-Myc的三种亚型中，全长c-Myc2蛋白表现出最大的拯救潜力，其次是c-Myc1，而缺乏反式激活结构域的c-MycS则没有。我们的研究表明，聚焦于c-Myc反式激活结构域的策略可能是设计针对多聚谷氨酰胺疾病的新型药物分子的非常有用的方法。
