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.