Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

Simone Bido, Sharon Muggeo, Luca Massimino, Matteo Jacopo Marzi, Serena Gea Giannelli, Elena Melacini, Melania Nannoni, Diana Gambarè, Edoardo Bellini, Gabriele Ordazzo, Greta Rossi, Camilla Maffezzini, Angelo Iannelli, Mirko Luoni, Marco Bacigaluppi, Silvia Gregori, Francesco Nicassio and Vania Broccoli ()
Additional contact information
Simone Bido: IRCCS San Raffaele Scientific Institute
Sharon Muggeo: IRCCS San Raffaele Scientific Institute
Luca Massimino: IRCCS San Raffaele Scientific Institute
Matteo Jacopo Marzi: Istituto Italiano di Tecnologia (IIT)
Serena Gea Giannelli: IRCCS San Raffaele Scientific Institute
Elena Melacini: IRCCS San Raffaele Scientific Institute
Melania Nannoni: IRCCS San Raffaele Scientific Institute
Diana Gambarè: IRCCS San Raffaele Scientific Institute
Edoardo Bellini: IRCCS San Raffaele Scientific Institute
Gabriele Ordazzo: IRCCS San Raffaele Scientific Institute
Greta Rossi: IRCCS San Raffaele Scientific Institute
Camilla Maffezzini: IRCCS San Raffaele Scientific Institute
Angelo Iannelli: IRCCS San Raffaele Scientific Institute
Mirko Luoni: IRCCS San Raffaele Scientific Institute
Marco Bacigaluppi: Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute
Silvia Gregori: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Francesco Nicassio: Istituto Italiano di Tecnologia (IIT)
Vania Broccoli: IRCCS San Raffaele Scientific Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26519-x

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