From the Cover: Arsenic Induces Accumulation of α-Synuclein: Implications for Synucleinopathies and Neurodegeneration.

Abstract

Synucleinopathies, including Parkinson's disease (PD), are neurodegenerative diseases characterized by accumulation of α-synuclein (SYN), a small neuronal protein with prion like properties that plays a central role in PD pathogenesis. SYN can misfold and generate toxic oligomers/aggregates, which can be cytotoxic. Environmental arsenic (As)-containing pesticide use correlates with increased incidence of PD. Moreover, because As exposure can lead to inhibition of autophagic flux we hypothesize that As can facilitate the accumulation of toxic SYN oligomers/aggregates and subsequent increases in markers of autophagy. We therefore examined the role of As in the oligomerization of SYN, and the consequences thereof. Chronic exposure of SH-SY5Y cells overexpressing SYN to As caused a dose-dependent oligomerization of SYN, with concomitant increases in protein ubiquitination and expression of other stress markers (protein glutathione binding, γ-GCS, light chain 3 (LC3)-I/II, P62, and NAD(P)H dehydrogenase quinone 1), indicative of an increased proteotoxic stress. Immunocytochemical analyses revealed an accumulation of SYN, and it's colocalization with LC3, a major autophagic protein. Mice exposed to As (100 ppb) for 1 month, exhibited elevated SYN accumulation in the cortex and striatum, and elevations in protein ubiquitination and LC3-I and II levels. However, tyrosine hydroxylase (TH), an indicator of dopaminergic cell density, was upregulated in the As exposed animals. Because SYN can inhibit TH function, and As can decrease monoamine levels, As exposure possibly leads to compensatory mechanisms leading to an increase in TH expression. Our findings suggest that susceptible individuals may be at higher risk of developing synucleinopathies and/or neurodegeneration due to environmental As exposure.

• Authors: Aram B Cholanians, Andy V Phan, Eric J Ditzel, Todd D Camenisch, Serrine S Lau, Terrence J Monks
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 153 Issue 2 Pg. 271-81 (10 2016) ISSN: 1096-0929 [Electronic] United States
• PMID: 27413109 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• alpha-Synuclein
• Arsenic

Topics

• Animals
• Arsenic (pharmacology)
• Cell Line
• Female
• Mice
• Neurodegenerative Diseases (metabolism)
• Parkinson Disease (metabolism)
• alpha-Synuclein (metabolism)