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Abstract
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.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 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.
Highlights
Parkinson's disease (PD) is the second most common neurodegenerative disease (Poewe et al, 2017). α-synuclein is the main constituent of Lewy bodies, which is an essential pathological marker for PD (Sharon et al, 2003)
Since PARK2 may significantly influence the characteristic of this patient, this patient was not included in the analysis of TGM6 carriers
Two TGM6 variants, c.331C > T (p.R111C) and c.1550T > G (p.L517W), were found in patients characterized by progressive ataxia and were found to affect the function of the protein transglutaminase 6 (TG6), such as the transglutaminase activity
Summary
Parkinson's disease (PD) is the second most common neurodegenerative disease (Poewe et al, 2017). α-synuclein is the main constituent of Lewy bodies, which is an essential pathological marker for PD (Sharon et al, 2003). Α-synuclein is the main constituent of Lewy bodies, which is an essential pathological marker for PD (Sharon et al, 2003). These aggregates of misfolded α-synuclein may eventually become toxic and trigger neuronal death. Autophagy is impaired in PD, leading to further accumulation of misfolded α-synuclein (Anglade et al, 1997; Cai et al, 2016). At least 17 genes have been identified as being associated with PD (http:// www.genenames.org). Risk loci for PD continue to be discovered by way of genome-wide association studies and other sequencing technologies (Chang et al, 2017; Shi et al, 2018)
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