TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis

Abstract

Neuropathology and Applied Neurobiology TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5-hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims: To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods: Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results: There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions: DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones.

The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration

“…However, a cohort study of blood/CNS tissue-based analysis showed significant association of DNA methylation with age of onset and survival in genetically unexplained ALS patients (Zhang et al, 2020). Assessment of post-mortem tissue from sporadic ALS (sALS) and C9orf72 ALS (C9ALS) cases showed high level of methylation and hydroxymethylation to a cytosine (5mC and 5hmC) in the residual lower motor neurones of the spinal cord (Appleby-Mallinder et al, 2021). These data suggesting DNA methylation as a contributory factor in ALS which need further focus.…”

Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

“…Further supporting a role for DNA methylation in ALS is the fact that DNA-(cytosine-5)-methyltransferase 3A (DNMT3A) was shown to be overexpressed in the brain and spinal cord of ALS patients, and this overexpression seems to be related to cell death in motor neuron like cells in vitro (Chestnut et al, 2011). In addition, TDP-43 has been related to uncommon DNA methylation (Appleby-Mallinder et al, 2020). However, methylation of the C9orf72 gene promoter is still controversial (Gijselinck et al, 2015;Bauer, 2016).…”

Roles of physical exercise in neurodegeneration: reversal of epigenetic clock

“…Only the CpGs located in proximity (within 2 kb) to the CAG expansion in exon 1 of HTT are significantly hypermethylated in HD, which exhibit positive correlations with severe motor progression in patients [ 164 , 165 ]. Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor neuron system, which is generally caused by mutations in the chromosome 9 open reading frame ( C9orf72 ) gene [ 166 ]. Hexanucleotide repeat expansion of C9orf72 causes downstream molecular aberrations and leads to overt cellular toxicity [ 167 ].…”