TGM6 (transglutaminase 6) is a cytoplasmic enzyme that catalyzes protein cross-linking through transamination reactions and conjugates polyamines to proteins 1. The enzyme is predominantly expressed in central nervous system neurons under physiological conditions 2 and is upregulated in reactive astrocytes during neuroinflammation 2. While TGM6 was initially proposed as a causative gene for spinocerebellar ataxia type 35 (SCA35), recent genetic analyses challenge this association. Multiple studies found TGM6 variants at similar frequencies in SCA patients, non-SCA patients, and healthy controls, with no significant allele frequency differences 3. Cumulative frequency analysis revealed reported pathogenic variants are inflated 111-fold over disease prevalence, suggesting high rates of misdiagnosis 4. Additionally, TGM6 variants identified in Parkinson's disease patients showed reduced transglutaminase activity but presented atypical disease progression 1. Beyond neurological contexts, TGM6 has been identified as a tuberculosis susceptibility locus; the rs6114027 risk allele correlates with decreased TGM6 transcripts and increased disease severity, with TGM6-deficient mice showing heightened infection susceptibility 5. Functionally distinct from its human homolog, parasitic TGM6 acts as a TGF-β antagonist selectively targeting fibroblasts and epithelial cells 6. In progressive multiple sclerosis, anti-TGM6 antibodies in cerebrospinal fluid correlate with disease activity and may serve as a biomarker 2.