Objective: To determine the relationship between synucleinopathy, neuroinflammation and nigrostriatal degeneration using the rat α-syn PFF model.

Background: No therapy exists to halt or slow nigrostriatal degeneration in Parkinson’s disease (PD). Neuroinflammatory markers are observed in post mortem PD brains, and longitudinal PET imaging reveals early microglial activation in the basal ganglia of PD patients. However, whether microglial-mediated neuroinflammation acts as a contributor to dopamine (DA) neuron loss or manifests as a consequence of nigrostriatal degeneration is debated. Our lab recently characterized a rat model in which intrastriatal injection of alpha-synuclein (α-syn) preformed fibrils (PFF) seed endogenous α-syn conversion into a pathological hyperphosphorylated form resulting in widespread, Lewy-body like pathology and ~40% nigral dopamine neuron degeneration over six months.   

Methods: Male Fischer 344 rats received unilateral intrastriatal injections of mouse α-syn PFFs or vehicle. Cohorts of rats (total n= 96) were euthanized at monthly intervals up to six months. Outcome measures at each time point include quantification of nigral dopamine neurons, phosphorylated α-syn (pS129) aggregates, microglial density (Iba-1) and major histocompatibility complex-II (MHC-II) antigen-presenting microglia.

Results: Significantly higher numbers of MHC-II-immunoreactive microglia were observed in the substantia nigra (SN) of α-syn PFF-injected rats compared to control rats, indicating that the neuroinflammation observed is pSyn inclusion-specific and not related to injection damage. Nigral MHC-II immunoreactivity peaked when: 1) phosphorylated α-syn accumulations were most abundant and 2) dopaminergic neurons began to lose their phenotype, events that occur prior to overt degeneration. 

Conclusions: These results suggest that pathological α-syn accumulation drives microglia-associated neuroinflammation prior to overt nigral degeneration and may serve as a contributor to nigral degeneration in PD. Future studies aimed at identifying specific inflammatory mediators will lead to greater understanding of the relationship of neuroinflammation to pathological α-syn misfolding and may identify future therapeutic targets for intervention

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuroinflammation-in-the-substantia-nigra-is-triggered-by-synucleinopathy-and-precedes-nigral-degeneration/