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

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.

Role of the endolysosomal system in Parkinson’s disease

“…Further understanding of the mechanisms for α‐synuclein‐autophagy crosstalk in PD might have crucial therapeutic applications. Backing this notion, both in vitro and in vivo studies show that enhancing autophagy and autophagosome‐lysosome fusion could ameliorate PD‐like features by clearing aggregated α‐synuclein (Suresh et al ; Suresh et al ).…”

“…Over-expression of a-synuclein also directly compromises macroautophagy through inhibition of Rab1a (Winslow et al 2010). It is also pertinent to note that aggregated a-synuclein in the soma is a key target of treatment strategies in development through induction of macroautophagy (Suresh et al 2017;Suresh et al 2018a).…”

Autophagic and endo-lysosomal dysfunction in neurodegenerative disease

“…Several mTOR-independent modifiers of autophagy are gaining interest as therapeutics, with AMPK activating molecules such as trehalose and metformin proving effective in reducing neurodegenerative phenotypes in models of AD [168, 169], ALS [170–172], HD [173, 174] and tauopathies [175]. Cellular targets not directly associated with the core autophagy machinery have also been found to modify neurodegeneration, including Estrogen Related Receptor α [176] and cAMP [177, 178]. Interestingly, the widely used AD-therapeutic memantine has emerged from a screen of clinically approved molecules which enhance autophagy [179], suggesting a potential mode of action for the drug which may be repurposed in other neurodegenerative disorders.…”

Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration

“…In PD, the continuous aggregate formation leads to an intracellular defect wherein proteostasis regulating mechanisms such as chaperones, Ubiquitin Proteasome System (UPS) and macroautophagy (henceforth autophagy) are impaired, leading to neuronal death [5]. Proof-of-principle experiments have demonstrated that clearing α-synuclein aggregates is beneficial and cytoprotective [6], [7], [8]. Toxic protein oligomers and aggregates are considered to be the substrates for autophagy machinery due to their size [9].…”