IMR Press / JIN / Volume 19 / Issue 1 / DOI: 10.31083/j.jin.2020.01.1203
Open Access Original Research
TGM6 variants in Parkinson’s disease: clinical findings and functional evidence
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1 Department of Neurology, Shanghai Tenth People’s Hospital, Tongji University, School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, P. R. China
2 Department of Neurology & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, P. R. China
*Correspondence: (Yan-Xin Zhao)
J. Integr. Neurosci. 2020, 19(1), 51–64;
Submitted: 6 October 2019 | Accepted: 28 January 2020 | Published: 30 March 2020
Copyright: © 2020 Chen et al. Published by IMR press.
This is an open access article under the CC BY-NC 4.0 license (

TGM6 encodes transglutaminase 6, which catalyzes the covalent crosslinking of proteins through transamination reactions. Variants in TGM6 have been identified as the cause of spinocerebellar ataxia type 35. However, we found 12 TGM6 variants of low frequency among 308 patients with Parkinson’s disease using next-generation sequencing technologies and multiple ligation-dependent probe amplification, including two variants TGM6 p.R111C and p.L517W, which have been reported to affect functions of transglutaminase 6 in spinocerebellar ataxia type 35 cases. The characteristics of these TGM6 carriers were summarized. To clarify the role of TGM6 variants in Parkinson’s disease, we constructed the plasmids of wild-type TGM6 and TGM6 p.R111C, p.359L, p.L517W to transfect A53T-SH-SY5Y cells and conducted transglutaminase assay, western blots, immunofluorescence, and cell viability assay. Results revealed that the distribution and expression levels of transglutaminase 6 were not affected by TGM6 variants. However, the variants showed lower transglutaminase activity than wild-type transglutaminase 6. The overexpression of wild-type TGM6 was proved to relieve the cell damage, down-regulate the level of α-synuclein and enhance autophagy. These effects were weakened in cells transfected with mutant TGM6 plasmids. Our results suggested that there may be some relationship between TGM6 and Parkinson’s disease. TGM6 carriers in Parkinson’s disease patients presented with typical parkinsonism but progressed slower. The high expression level of wild-type transglutaminase 6 may protect cells by decreasing α-synuclein and enhancing autophagy.

Parkinson’s disease
genetic testing
transglutaminase 6
Figure 1.
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