Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease leading to degeneration of motor neurons (MNs). Epigenetic modification of gene expression is increasingly recognized as potential disease mechanism. In the present study we generated motor neurons from induced pluripotent stem cells from ALS patients carrying a mutation in the fused in sarcoma gene (FUS) and analyzed expression and promoter methylation of the FUS gene and expression of DNA methyltransferases (DNMTs) compared to healthy control cell lines. While mutant FUS neural progenitor cells (NPCs) did not show a difference in FUS and DNMT expression compared to healthy controls, differentiated mutant FUS motor neurons showed significantly lower FUS expression, higher DNMT expression and higher methylation of the proximal FUS gene promoter. Immunofluorescence revealed perceived proximity of cytoplasmic FUS aggregates in ALS MNs together with 5-methylcytosin (5-mC). Targeting disturbed methylation in ALS may therefore restore transcriptional alterations and represent a novel therapeutic strategy.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system leading to death after 3–5 years from symptom onset, mainly due to respiratory insufficiency (Talbot, 2009)
To further confirm the immunofluorescence observations, neural progenitor cells (NPCs) and motor neurons (MNs) were analyzed for mRNA expression of neuronal- and MN-specific markers by quantitative RT-PCR
Even though controversial data have been reported in relation to different ALS causing genes and sporadic ALS cases, the majority of studies come to the conclusion that global DNA methylation is increased in ALS (Chestnut et al, 2011; Tremolizzo et al, 2014)
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system leading to death after 3–5 years from symptom onset, mainly due to respiratory insufficiency (Talbot, 2009). Protein aggregate pathology shows a characteristic spreading pattern across specific brain regions with disease progression, suggesting a “prion-like” spreading mechanism (Brettschneider et al, 2013). Up to date this multifactorial process is not fully understood. Excitotoxicity, disturbed RNA transport and splicing, axonal protein transport and mitochondrial function appear to be involved. While this process may be initiated by distinct monogenetic mutations in the 10% familial cases, its precise pathophysiology in the 90% sporadic cases is still unclear. Epigenetic and post-transcriptional modifications are getting more attention in this context
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