Transglutaminase 2 depletion attenuates α-synuclein mediated toxicity in mice

Zhang, Jie and Jasutkar, Hilary Grosso and Yan, Run and Woo, Jong-Min and Lee, Kang-Woo and Im, Joo-Young and Junn, Eunsung and Iismaa, Siiri E. and Mouradian, M. Maral (2020) Transglutaminase 2 depletion attenuates α-synuclein mediated toxicity in mice. Neuroscience. ISSN 03064522

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α-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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 08 Jun 2020 23:25
Last Modified: 08 Nov 2021 02:38

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