Suresh S N, Chavalmane Aravinda K, Pillai Malini, Ammanathan Veena, Vidyadhara D J, Yarreiphang Haorei, Rai Shashank, Paul Abhik, Clement James P, Alladi Phalguni A, Manjithaya Ravi
Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Front Mol Neurosci. 2018 Apr 9;11:109. doi: 10.3389/fnmol.2018.00109. eCollection 2018.
Mechanistic insights into aggrephagy, a selective basal autophagy process to clear misfolded protein aggregates, are lacking. Here, we report and describe the role of Estrogen Related Receptor α (ERRα, HUGO Gene Nomenclature ESRRA), new molecular player of aggrephagy, in keeping autophagy flux in check by inhibiting autophagosome formation. A screen for small molecule modulators for aggrephagy identified ERRα inverse agonist XCT 790, that cleared α-synuclein aggregates in an autophagy dependent, but mammalian target of rapamycin (MTOR) independent manner. XCT 790 modulates autophagosome formation in an ERRα dependent manner as validated by siRNA mediated knockdown and over expression approaches. We show that, in a basal state, ERRα is localized on to the autophagosomes and upon autophagy induction by XCT 790, this localization is lost and is accompanied with an increase in autophagosome biogenesis. In a preclinical mouse model of Parkinson's disease (PD), XCT 790 exerted neuroprotective effects in the dopaminergic neurons of nigra by inducing autophagy to clear toxic protein aggregates and, in addition, ameliorated motor co-ordination deficits. Using a chemical biology approach, we unrevealed the role of ERRα in regulating autophagy and can be therapeutic target for neurodegeneration.
目前仍缺乏对聚集体自噬（一种清除错误折叠蛋白聚集体的选择性基础自噬过程）的机制性认识。在此，我们报告并描述了雌激素相关受体α（ERRα，人类基因命名法为ESRRA）作为聚集体自噬的新分子参与者，通过抑制自噬体形成来控制自噬通量的作用。一项针对聚集体自噬小分子调节剂的筛选鉴定出ERRα反向激动剂XCT 790，它以自噬依赖性但不依赖雷帕霉素哺乳动物靶标（MTOR）的方式清除α-突触核蛋白聚集体。如通过小干扰RNA介导的敲低和过表达方法所验证的，XCT 790以ERRα依赖性方式调节自噬体形成。我们发现，在基础状态下，ERRα定位于自噬体上，而在XCT 790诱导自噬后，这种定位消失，并伴随着自噬体生物合成增加。在帕金森病（PD）的临床前小鼠模型中，XCT 790通过诱导自噬清除有毒蛋白聚集体，对黑质中的多巴胺能神经元发挥神经保护作用，此外，还改善了运动协调缺陷。通过化学生物学方法，我们揭示了ERRα在调节自噬中的作用，并且它可能是神经退行性疾病的治疗靶点。
