SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.

Background Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methods Methylation levels were determined by pyrosequencing of bisulfite treated DNA in a leukocyte cohort (358 PD and 1084 controls) and two brain cohorts (Brain1 comprising 69 cerebellum controls, Brain2 comprising 3 brain regions from 28 PD and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. Results In normal leukocytes, MAPT H1/H2 diplotype and gender were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed H1 haplotype to have higher methylation than H2 in normal leukocyte and brain tissues. MAPT methylation was negatively associated with MAPT expression in Brain1 cohort and transfected cells. Methylation levels differed between three normal brain regions (Brain2, putamen > cerebellum > anterior cingulate cortex). In PD samples, age at onset was positively associated with MAPT methylation in leukocytes. Moreover, there was hypermethylation in the cerebellum and hypomethylation in the putamen of PD patients compared with controls (Brain2 cohort). Finally, leukocyte methylation status was positively associated with blood Vitamin E levels, the effect being more significant in H2 haplotype carriers; this result was confirmed in cells exposed to 100 mM Vitamin E. Conclusions The significant effects of gender, diplotype and brain region suggest that hypermethylation of the MAPT is neuroprotective by reducing MAPT expression. Vitamin E effect on MAPT represents a possible gene-environment interaction.

Studies investigating the pathogenic role of the microtubule associated protein tau (MAPT) gene in Parkinson’s disease (PD) have indicated that DNA methylation of the promoter region is aberrant in disease, leading to dysregulated MAPT expression. We examined two potential regulators of MAPT gene expression in respect to PD, a promoter-associated long non-coding RNA MAPT-AS1, and DNA methyltransferases (DNMTs), enzymes responsible for new and maintenance of DNA methylation. We assessed the relationship between expression levels of MAPT and the candidate MAPT-AS1, DNMT1, DNMT3A and DNMT3B transcripts in four brain regions with varying degrees of cell loss and pathology (putamen, anterior cingulate cortex, visual cortex and cerebellum) in N = 10 PD and N = 10 controls. We found a significant decrease in MAPT-AS1 expression in PD (p = 7.154 x 10−6). The transcript levels of both MAPT-AS1 (p = 2.569 x 10−4) and DNMT1 (p = 0.001) correlated with those of MAPT across the four brain regions, but not with each other. Overexpression of MAPT-AS1 decreased MAPT promoter activity by ∼2.2 to 4.3 fold in an in vitro luciferase assay performed in two cell lines (p ≤ 2.678 x 10−4). Knock-down expression of MAPT-AS1 led to a 1.3 to 6.3 fold increase in methylation of the endogenous MAPT promoter (p ≤ 0.011) and a 1.2 to 1.5 fold increased expression of the 4-repeat MAPT isoform transcript (p ≤ 0.013). In conclusion, MAPT-AS1 and DNMT1 have been identified as potential epigenetic regulators of MAPT expression in PD across four different brain regions. Our data also suggest that increased MAPT expression could be associated with disease state, but not with PD neuropathology severity.