UCLA

Parkinson's Disease (PD) is a common, disabling neurodegenerative disorder neuropathologically defined by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the accumulation of intracellular Lewy body inclusions. Lewy body inclusions are primarily composed of misfolded alpha-synuclein fibrils. Multiple lines of evidence from human autopsy studies and animal models suggest that misfolded ɑ-Syn aggregates can be transferred between neurons, propagating ɑ-Syn pathology throughout the brain in a prion-like manner. However, ɑ-Syn pathology does not spread diffusely, but rather certain brain regions display a selective vulnerability to ɑ-Syn aggregate formation. Levels of ɑ-Syn expression and anatomical connectivity partially explain the observed regional vulnerability, but additional factors must be involved as well. We hypothesized that certain types of neurons may be more likely to form ɑ-Syn pathology than others. To investigate whether there is a cell type specific vulnerability for ɑ-Syn aggregate formation, we used the pre-formed fibril (PFF) model of PD. Specifically, we injected ɑ-Syn PFFs directly into either the primary motor cortex or the dorsolateral striatum. We then used immunofluorescence staining to quantify pathological ɑ-Syn aggregates and to co-localize these with markers for specific neuronal subpopulations. We found that injection of ɑ-Syn PFFs leads to the local accumulation of pathological ɑ-Syn aggregates. In both the cortex and dorsolateral striatum, non-somatically localized aggregates were more numerous than somatically localized aggregates. In the cortex, we observed somatic ɑ-Syn aggregates colocalizing with excitatory neurons and inhibitory interneurons. A greater proportion of inhibitory interneurons colocalized with somatic ɑ-Syn aggregates than excitatory neurons. Furthermore, in the dorsolateral striatum, both D1 and D2 medium spiny neurons (MSNs) colocalized with somatic ɑ-Syn aggregates, with a higher proportion of D1 MSNs colocalizing with somatic ɑ-Syn compared to D2 MSNs. These results suggest that there may be some mechanisms contributing to a cell-type vulnerability for ɑ-Syn aggregate formation. Further research investigating these mechanisms may offer new approaches for therapeutic disease intervention in PD.