| First Author | Zhang J | Year | 2020 |
| Journal | Neuroscience | Volume | 441 |
| Pages | 58-64 | PubMed ID | 32502569 |
| Mgi Jnum | J:298658 | Mgi Id | MGI:6478565 |
| Doi | 10.1016/j.neuroscience.2020.05.047 | Citation | Zhang J, et al. (2020) Transglutaminase 2 Depletion Attenuates alpha-Synuclein Mediated Toxicity in Mice. Neuroscience 441:58-64 |
| abstractText | alpha-Synuclein (alpha-Syn) is a key pathogenic protein in alpha-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of alpha-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 alpha-Syn toxicity in mice and yeast by increasing the higher-order species of alpha-Syn. Herein, we investigated whether deletion of the TG2 encoding gene could mitigate the toxicity of alpha-Syn in vivo. Compared with alpha-Syn transgenic (Syn(Tg)) mice, TG2 null /alpha-Syn transgenic mice (TG2(KO)/Syn(Tg)) exhibited a reduced amount of phosphorylated alpha-Syn aggregates and fewer proteinase K-resistant alpha-Syn aggregates in sections of brain tissue. Neuritic processes that are depleted in Syn(Tg) mice compared to wild-type mice were preserved in double TG2(KO)/Syn(Tg) mice. Additionally, the neuroinflammatory reaction to alpha-Syn was attenuated in TG2(KO)/Syn(Tg) animals. These neuropathological markers of diminished alpha-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 alpha-Syn in vivo and improves the behavioral performance of Syn(Tg) mice. Accordingly, these findings collectively support pharmacological inhibition of TG2 as a potential disease modifying therapeutic strategy for alpha-synucleinopathies. |
