A novel autophagy modulator 6-Bio ameliorates SNCA/α-synuclein toxicity

Suresh, Shwetha; Chavalmane, Aravinda K.; Vidyadhara, D J; Yarreiphang, Haorei; Rai, Shashank; Paul, Abhik; Clement, James P.; Alladi, Phalguni Anand; Manjithaya, Ravi

doi:10.1080/15548627.2017.1302045

Cited by 58 publications

(44 citation statements)

References 40 publications

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“…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 ).…”

Section: Autophagy In Pd; Cause and Effect Hand In Handmentioning

confidence: 99%

“…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).…”

Section: Pink1 and Parkin: Role In Mitophagy And Beyondmentioning

confidence: 99%

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Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

111

105

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E‐L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin‐mediated synaptic endocytosis, an integral part of the neuronal E‐L system, is probably the main early target as evident in auxilin, RME‐8, and synaptojanin‐1 mutations that cause PD. Autophagy, another important pathway in the E‐L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life‐time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi‐compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α‐synuclein and LRRK2, key proteins involved in PD, function in different steps of the E‐L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E‐L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue “Synuclein”.

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Section: Autophagy In Pd; Cause and Effect Hand In Handmentioning

confidence: 99%

Section: Pink1 and Parkin: Role In Mitophagy And Beyondmentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

111

105

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“…Toxic protein aggregates and intracellular pathogens are known to be substrates of the autophagy pathway for their effective cellular degradation (Deretic and Levine, 2009 ; Nixon, 2013 ). 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.…”

Section: Resultsmentioning

confidence: 99%

“…Autophagy is shown to be dysfunctional during the neurodegenerative disease pathology (Nixon, 2013 ). Thus, restoration of autophagy through pharmacological approaches using small molecules has been reported to be neuroprotective (Sarkar et al, 2007 ; Khurana and Lindquist, 2010 ; Rajasekhar et al, 2015 ; Suresh et al, 2017 ). Small molecule that induces or restores defunct autophagy could aid in toxic aggregate clearance and essential for maintaining the cellular and organismal homeostasis (Rajasekhar et al, 2014 , 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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

Suresh

Chavalmane

Pillai

et al. 2018

Front. Mol. Neurosci.

Self Cite

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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.

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“…Impairment of the autophagy-lysosomal pathway in the diseased brain has been shown to not only limit intracellular degradation of misfolded SNCA aggregates but also to lead to a detrimental microenvironmental response due to enhanced SNCA secretion, thus promoting PD pathology [ 31 ]. A neuroprotective modulator, 6-Bio, could clear the toxic SNCA aggregates by dramatically enhancing autolysosomal formation in yeast and mammalian cell lines [ 32 ]. Nilotinib, a brain-penetrant tyrosine kinase inhibitor, also facilitates the autophagic clearance of SNCA in transgenic and lentiviral gene transfer models, thus improving the major PD symptoms [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

SNCA Is a Functionally Low-Expressed Gene in Lung Adenocarcinoma

Yan

et al. 2018

Genes

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There is increasing evidence for the contribution of synuclein alpha (SNCA) to the etiology of neurological disorders, such as Parkinson’s disease (PD). However, little is known about the detailed role of SNCA in human cancers, especially lung cancers. Here, we evaluated the effects of SNCA on the occurrence and prognosis of lung adenocarcinoma (ADC). Comprehensive bioinformatics analyses of data obtained from the Oncomine platform, the human protein atlas (HPA) project and the cancer cell line encyclopedia (CCLE) demonstrated that SNCA expression was significantly reduced in both ADC tissues and cancer cells. The results of relevant clinical studies indicated that down-regulation of SNCA was statistically correlated with shorter overall survival time and post-progression survival time. Through analysis of datasets obtained from the Gene Expression Omnibus database, significant low levels of SNCA were identified in cisplatin-resistant ADC cells. Moreover, small interfering RNA (siRNA)-mediated knockdown of protein tyrosine kinase 7 (PTK7) elevated the expression of SNCA in the ADC cell lines H1299 and H2009. Our work demonstrates that low levels of SNCA are specifically found in ADC and that this gene may be a potential therapeutic target for this subset of lung cancers. Determination of the role of SNCA in ADC biology would give us some insightful information for further investigations.

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A novel autophagy modulator 6-Bio ameliorates SNCA/α-synuclein toxicity

Cited by 58 publications

References 40 publications

Role of the endolysosomal system in Parkinson’s disease

Role of the endolysosomal system in Parkinson’s disease

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

SNCA Is a Functionally Low-Expressed Gene in Lung Adenocarcinoma

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