EARLY Α-SYNUCLEIN PATHOLOGY IN MICE LEADS TO MOTOR DYSFUNCTION, DIFFERENTIAL MICROGLIA CLUSTERS AND ALTERED IMMUNE SIGNALING

Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disorder and has received considerable attention in neuroscience research. However, early stages of PD have remained relatively unexplored, despite symptoms, such as depression and anxiety, often occurring years before diagnosis. PD pathology is associated with accumulation of alpha-Synuclein (αSyn), loss of dopamine neurons and accumulation of microglia in the Substantia Nigra pars compacta (SNpc). The aim of this study is to explore Immune-to-Brain mechanisms in early stages of PD, when behavioral and neuropathological symptoms arise.
We developed an early PD mouse model using a ‘low dose’ Adeno-Associated Viral (AAV) strategy, for overexpression of human αSyn in SNpc. We found that early PD αSyn-mice exhibit locomotor dysfunction and negative affective state compared to controls. No detectable loss of TH+ dopaminergic somas was present in the αSyn mice; however, TH-expression was significantly decreased in striatum, suggesting synaptic disintegration. αSyn mice showed increased numbers of IBA1+ reactive microglia in SNpc, and single nuclei RNA sequencing (snRNA-seq) revealed a shift from homeostatic to reactive microglia and DAMs. Microglia in αSyn mice exhibited a marked inflammatory profile, including interferon response and major histocompatibility complexes class I and II activation. We further identified, using snRNA-seq and flow cytometry, infiltration of Double Negative T cells (DNTs) in the αSyn mice – which has not previously been reported in models of Parkinson’s Disease. LIANA+ cell-cell communication analysis revealed that microglia and DNTs exhibit reciprocal signaling. We are currently exploring strategies for in vivo targeting of T cells and microglia reactivity.