Abstract
Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.
Highlights
Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease
Pathological αSYN aggregation was detectable in microglia in these mice, DA neurons did not show any evidence of αSYN accumulation, indicating that DA neuronal degeneration was largely independent of this pathological mechanism
Since APOE ε4 was shown to directly exacerbate αSYN pathology and reactive gliosis in Parkinson’s disease (PD) mice[45], it is plausible that a vicious loop between inflamed microglia and the APOE genotype can strongly contribute to neurodegeneration
Summary
Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease. To better determine the primary role of microglial cells in PD onset and progression and to describe the effects triggered by the diseased microglia in an otherwise healthy tissue, we developed a mouse model with selective αSYN accumulation in nigral microglia. With this approach we unveiled the primary neurotoxicity of these cells which caused the selective degeneration of the surrounding DA neurons. We provided a description at single-cell resolution of the infiltrated immune cells and the αSYN-accumulating microglia which identified immune cell populations whose pathological significance will be addressed in the future using this experimental system
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