Key Connectomes and Synaptic-Compartment-Specific Risk Genes Drive Pathological α-Synuclein Spreading.

Area of Science:

• Neuroscience
• Computational Biology
• Genetics

Background:

• Pathological alpha-synuclein (α-Syn) spread along neuronal networks is implicated in neurodegenerative diseases.
• Key questions remain regarding the specific connections and genes driving this pathological spread.

Purpose of the Study:

• To identify critical connections in the brain's connectome that predict pathological α-Syn progression.
• To pinpoint risk genes involved in α-Syn pathology spreading at presynaptic and postsynaptic regions.
• To investigate the cellular enrichment of these risk genes.

Main Methods:

• Novel mathematical models were employed to analyze the connectome and pathological α-Syn transmission.
• Gene regulatory network analysis was used to identify key drivers of selective vulnerability.
• Analysis distinguished between presynaptic and postsynaptic gene functions.

Main Results:

• Pathological α-Syn spread is predominantly determined by a small subset (2%) of the strongest connections.
• Risk genes are significantly enriched in microglial cells (presynaptic) and neurons (postsynaptic).
• Key drivers of selective vulnerability overlap with Parkinson's disease risk genes.

Conclusions:

• The study identifies critical subnetworks and risk genes governing pathological α-Syn spread.
• Distinct functional roles of presynaptic and postsynaptic genes in α-Syn transmission are demonstrated.
• This provides novel insights into the mechanisms underlying neurodegenerative disease progression.