TGM6 encodes transglutaminase 6, which catalyzes the covalent crosslinking of proteins via transamination reactions [1]. It has also been identified as a natural antagonist of mammalian TGF-β signaling produced by the murine helminth parasite Heligmosomoides polygyrus, mimicking TGF-β binding to TGFBR2 in fibroblasts [3,5].

TGM6 variants have been associated with spinocerebellar ataxia type 35, but there are doubts about its role as a specific causative gene [4,6]. In Parkinson's disease, 12 low-frequency TGM6 variants were found among 308 patients. Mutant TGM6 plasmids showed lower transglutaminase activity than wild-type, and the protective effects of wild-type TGM6 on cells, such as reducing α-synuclein and enhancing autophagy, were weakened in cells transfected with mutant plasmids [1]. A study questioned the pathogenicity of the TGM6 p.L517W variant in spinocerebellar ataxia 35 as it did not segregate with the phenotype [2]. Genetic analysis also indicated that TGM6 might not be a specific causative gene for spinocerebellar ataxia, as the allele frequencies of its variants did not differ among spinocerebellar ataxia patients and controls, and reported pathogenic variants were found in patients with various neurologic diseases or normal controls [4].

In conclusion, TGM6 has functions in protein cross-linking and modulating TGF-β signaling. Its role in spinocerebellar ataxia type 35 is uncertain, while in Parkinson's disease, TGM6 variants may be related to the disease with potential impacts on cellular protective mechanisms. Further research is needed to clarify its exact functions and roles in these neurological conditions.

References:

1. Chen, Kui, Lu, You, Peng, Fang, Tan, Yan, Zhao, Yan-Xin. . TGM6 variants in Parkinson's disease: clinical findings and functional evidence. In Journal of integrative neuroscience, 19, 51-64. doi:10.31083/j.jin.2020.01.1203. https://pubmed.ncbi.nlm.nih.gov/32259886/

2. Chen, Yanxing, Wu, Dengchang, Luo, Benyan, Zhao, Guohua, Wang, Kang. 2020. TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35. In Neurology. Genetics, 6, e424. doi:10.1212/NXG.0000000000000424. https://pubmed.ncbi.nlm.nih.gov/32426513/

3. White, Stephen E, Schwartze, Tristin A, Mukundan, Ananya, Maizels, Rick M, Hinck, Andrew P. 2023. TGM6, a helminth secretory product, mimics TGF-β binding to TβRII to antagonize TGF-β signaling in fibroblasts. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.12.22.573140. https://pubmed.ncbi.nlm.nih.gov/38187573/

4. Cheng, Hao-Ling, Dong, Hai-Lin, Liu, De-Shan, Dong, Yi, Wu, Zhi-Ying. 2021. TGM6 might not be a specific causative gene for spinocerebellar ataxia resulting from genetic analysis and functional study. In Gene, 779, 145495. doi:10.1016/j.gene.2021.145495. https://pubmed.ncbi.nlm.nih.gov/33588035/

5. White, Stephen E, Schwartze, Tristin A, Mukundan, Ananya, Maizels, Rick M, Hinck, Andrew P. 2025. TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. In Nature communications, 16, 1847. doi:10.1038/s41467-025-56954-z. https://pubmed.ncbi.nlm.nih.gov/39984487/

6. Fung, Jasmine L F, Tsang, Mandy H Y, Leung, Gordon K C, Yu, Mullin H C, Chung, Brian H Y. 2019. A significant inflation in TGM6 genetic risk casts doubt in its causation in spinocerebellar ataxia type 35. In Parkinsonism & related disorders, 63, 42-45. doi:10.1016/j.parkreldis.2019.01.013. https://pubmed.ncbi.nlm.nih.gov/30670339/