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- Jie Zhang, Grosso JasutkarHilaryHRobert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, Piscataway, NJ 08854, USA., Run Yan, Jong-Min Woo, Kang-Woo Lee, Joo-Young Im, Eunsung Junn, Siiri E Iismaa, and M Maral Mouradian.
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, Piscataway, NJ 08854, USA.
- Neuroscience. 2020 Aug 10; 441: 58-64.
Abstractα-Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of α-Syn is believed to be deleterious and a critical step leading to neuronal dysfunction and death. One of the factors that may contribute to the initial steps of this aggregation is crosslinking through transglutaminase 2 (TG2). We previously demonstrated that overexpression of TG2 exacerbates α-Syn toxicity in mice and yeast by increasing the higher-order species of α-Syn. Herein, we investigated whether deletion of the TG2 encoding gene could mitigate the toxicity of α-Syn in vivo. Compared with α-Syn transgenic (SynTg) mice, TG2 null /α-Syn transgenic mice (TG2KO/SynTg) exhibited a reduced amount of phosphorylated α-Syn aggregates and fewer proteinase K-resistant α-Syn aggregates in sections of brain tissue. Neuritic processes that are depleted in SynTg mice compared to wild-type mice were preserved in double TG2KO/SynTg mice. Additionally, the neuroinflammatory reaction to α-Syn was attenuated in TG2KO/SynTg animals. These neuropathological markers of diminished α-Syn toxicity in the absence of TG2 were associated with better motor performance on the rotarod and balance beam. These results suggest that deleting TG2 reduces the toxicity of α-Syn in vivo and improves the behavioral performance of SynTg mice. Accordingly, these findings collectively support pharmacological inhibition of TG2 as a potential disease modifying therapeutic strategy for α-synucleinopathies.Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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