Poster Presentation 46th Lorne Genome Conference 2025

Changes to midbrain microglia lipid regulation in a model of chronic inflammation (#148)

Isabel A Hemming 1 , behzad Yaghmaeian Salmani 1 , Linda Gillberg 1 , Laura Lahti 1 , Thomas Perlmann 1
  1. Karolinska Institutet, Stockholm, STOCKHOLM, Sweden

Parkinson’s disease (PD) is a neurodegenerative disorder marked by the degeneration of midbrain dopamine neurons leading to phenotypical motor symptoms, such as tremors. Dopamine neurons present within the substantia nigra pars compacta (SNpc) are especially sensitive to degeneration. A critical element in PD pathology is the protein alpha-synuclein (aSyn), which is phosphorylated and involved in forming abnormal protein aggregates, known as Lewy bodies. Recent research highlights the role of microglia in various neurodegenerative diseases, positioning them as a promising therapeutical target in PD.
In our study, we employed a mouse model expressing a modified form of aSyn that accelerates phosphorylation and aggregation, resulting in early-onset PD-like symptoms responsive to L-DOPA, a dopamine precursor commonly used in replacement therapy for the management of PD. Initial histological examination indicated significant microglial infiltration around midbrain dopamine neurons, including within the SNpc. To further examine these midbrain microglia, we performed fluorescence-activated cell sorting (FACS) on microdissected midbrain tissue, isolating CD45+ microglia for single-cell RNA sequencing (scRNA-seq).
Our analysis showed elevated microglial presence in PD-like mice and identified a distinct disease-associated microglia population exhibiting a chronic inflammatory transcriptional profile, likely driven by sustained aSyn phosphorylation and aggregation. Further validation within midbrain tissue confirmed these transcriptional signatures. Within this population, we identified a subgroup enriched in genes linked to lipid function. These genes are known to bind, modify, and metabolise lipids, implicating lipid dysregulation as a secondary effect of chronic inflammation.
These findings suggest that persistent midbrain inflammation, accompanied by lipid dysregulation, may play a critical role in PD progression. Our study highlights microglial lipid metabolism as a potential pathway for developing interventions aimed at modulating neu-roinflammation in PD.