TGM6 variants in Parkinson's disease: clinical findings and functional evidence

encodes transglutaminase 6, which catalyzes the covalent crosslinking of proteins through transamination reactions. Variants in have been identified as the cause of spinocerebellar ataxia type 35. However, we found 12 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 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 carriers were summarized. To clarify the role of variants in Parkinson's disease, we constructed the plasmids of wild-type and p.R111C, p.P359L, 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 variants. However, the variants showed lower transglutaminase activity than wild-type transglutaminase 6. The overexpression of wild-type 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 plasmids. Our results suggested that there may be some relationship between and Parkinson's disease. 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.