Abstract: Beyond its direct neuronal effects, alpha-synuclein (α-synuclein) interacts with microglia, influencing disease progression through mechanisms that are not fully understood. Microglia may contribute to the propagation of α-synuclein pathology through pathophysiological pathways such as incomplete degradation and intercellular transfer of aggregates. Research into α-synuclein-microglia interactions has revealed their dual role in aggregate clearance and inflammation, highlighting microglia as both protective and deleterious agents in synucleinopathies. Human genetics suggest that neuronal-glial crosstalk plays a causal role in α-synucleinopathies. Leucine-rich repeat kinase 2 (LRRK2) may originate in the microglia based on studies with induced pluripotent stem cells (iPSCs). Other IPSC-derived microglia were glycoprotein nonmetastatic melanoma protein B and lysolipid transporter 1 (SPNS1) in Parkinson’s disease (PD). Another source of α-synuclein could be neuronal, and the discovery of cyclic guanosine monophosphate–adenosine monophosphate (AMP) synthase/stimulator of interferon genes leading to stimulation of interferons and LRRK2, especially in dopamine neurons, is a supporting finding. Multiple system atrophy (MSA) is an oligodendroglial disease, and some of the targets for management may involve mitochondrial dysfunction, iron deposition, lipid droplets, cytoskeleton disruption, proteasome dysfunction, and tubulin polymerization, promoting protein-like proteins containing p25α. The aim of this review is to provide a comprehensive overview of the molecular and cellular mechanisms linking α-synuclein and microglial activation in PD and MSA, with a focus on genetic insights, autophagy-related pathways, and emerging therapeutic targets.
Rissardo et al. (Mon,) studied this question.