Epigenetic and Transcriptomic Alterations of Protein Aggregation-Linked Genes in Suicide: A Pilot Study

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Suicide is a complex public health issue with poorly understood biological underpinnings.
• Epigenetic factors and protein aggregation (proteinopathy) are implicated in psychiatric disorders and suicidality.
• The interplay between epigenetics and proteinopathy in suicide remains largely unexplored.

Purpose of the Study:

• To investigate epigenetic and transcriptional alterations in protein aggregation-related genes in post-mortem brain samples from individuals who died by suicide.
• To explore the potential role of proteostasis disturbances in the biological mechanisms of suicide.

Main Methods:

• Analysis of genome-wide DNA methylation (using reduced representation bisulfite sequencing - RRBS) and gene expression (using qPCR) in post-mortem hippocampal and Brodmann area 46 brain tissue.
• Comparison between 32 suicide cases (hanging) and 37 sudden cardiac death controls.
• Identification of differentially methylated cytosines (DMCs) and gene expression levels in candidate aggregation-related genes.

Main Results:

• Hypomethylation was observed in suicide cases within several aggregation-related genes, including CRMP1, DISC1, MAPT, SOD1, PRKN, GABARAPL1, GRIN2A, and GRIN2B.
• In the hippocampus, increased expression of CRMP1, SOD1, PRKN, GABARAPL1, and GRIN2A, along with decreased MAPT expression, was noted in suicides.
• An elevated GRIN2A/GRIN2B expression ratio and altered expression in Brodmann area 46 (increased GRIN2A, decreased DISC1) were also found.

Conclusions:

• This pilot study provides the first evidence linking epigenetic and transcriptional dysregulation of protein aggregation-associated genes to suicide.
• Findings suggest that disturbances in proteostasis may contribute to suicidality, particularly involving hippocampal pathways regulating stress response and synaptic signaling.
• Further validation in larger cohorts and protein-level studies are necessary to elucidate the functional significance of these epigenetic and transcriptional changes in suicide.