Modulation of Autophagy by a Small Molecule Inverse Agonist of ERRα Is Neuroprotective.

S N Suresh,Shashank Rai,Haorei Yarreiphang,Malini Pillai,Aravinda K Chavalmane,Ravi Manjithaya,Phalguni A Alladi,Abhik Paul,Veena Ammanathan,James P Clement,D J Vidyadhara

doi:10.3389/fnmol.2018.00109

Abstract

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.

Highlights

Proteostasis machineries associated with the clearance of various cellular cargos including toxic proteins and damaged organelles in eukaryotic cells primarily include the chaperone, the Ubiquitin–Proteasome System (UPS), and the autophagy pathways (Hipp et al, 2014)
Based on a previous small molecule screening for aggrephagy inducers from our laboratory (Suresh et al, 2017), we identified thiadiazoleacrylamide, XCT 790, as a drug-like molecule that abrogates α-synuclein cellular toxicity, and intracellular Salmonella typhimurium
We tested the potential of XCT 790 to clear toxic α-synuclein protein aggregates, and Salmonella burden through autophagy in mammalian cells such as human neuroblastoma SH-SY5Y and HeLa cell lines

Summary

Introduction

Proteostasis machineries associated with the clearance of various cellular cargos including toxic proteins and damaged organelles in eukaryotic cells primarily include the chaperone, the Ubiquitin–Proteasome System (UPS), and the autophagy pathways (Hipp et al, 2014). UPS predominantly degrades short-lived proteins via tagging them with ubiquitin at specific amino acid residues (Hipp et al, 2014). The bulk degradation of long-lived proteins or organelles is mediated largely by the evolutionarily conserved cellular process referred to as macroautophagy (hereafter autophagy). A selective degradation mechanism called aggrephagy can help cells to clear the toxic, long-lived, aggregate-prone proteins. Misfolded and aggregate prone proteins are substrates for autophagy (Nixon, 2013). Intracellular accumulation of misfolded protein aggregates is an evident feature of several neurodegenerative diseases including Parkinson’s

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