Alpha-Synuclein-induced DNA Methylation and Gene Expression in Microglia.

Area of Science:

• Neuroscience
• Immunology
• Genomics

Background:

• Synucleinopathy disorders involve alpha-synuclein (α-syn) aggregates that activate microglia, causing neuroinflammation.
• Understanding microglial responses to α-syn is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate gene expression and DNA methylation changes in microglia induced by aggregated α-syn in a mouse model.
• To elucidate the functional consequences of these molecular changes on microglial phenotype and activity.

Main Methods:

• Utilized transgenic Thy-1 promoter (mThy1)-Asyn mice overexpressing human α-syn.
• Performed methylated DNA and RNA-sequencing on microglia from 3 and 13-month-old mice.
• Conducted functional enrichment and network analysis on differentially methylated genes (DMGs) and differentially expressed genes (DEGs).

Main Results:

• At 3 months, significant changes in gene expression (119 DEGs) and methylation (5315 DMGs) were associated with microglial adhesion and migration.
• At 13 months, a larger number of DMGs (3742) and DEGs (3766) were linked to cell cycle, metabolism, and immune response.
• Network analysis indicated a shift from increased cell mobility and inflammation at 3 months to cell cycle, immune response, and metabolism alterations at 13 months.

Conclusions:

• Alpha-synuclein overexpression induces significant methylation and gene expression changes in microglia.
• These molecular alterations suggest α-syn initiates microglial activation, leading to neuroinflammation and metabolic stress.
• The findings provide insights into the role of microglial dysfunction in synucleinopathy progression.