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

Author

Listed:
  • 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
    Institute of Neuroscience)

  • 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
    Institute of Neuroscience)

  • 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
    Institute of Neuroscience)

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.

Suggested Citation

  • Simone Bido & Sharon Muggeo & Luca Massimino & Matteo Jacopo Marzi & Serena Gea Giannelli & Elena Melacini & Melania Nannoni & Diana Gambarè & Edoardo Bellini & Gabriele Ordazzo & Greta Rossi & Camill, 2021. "Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26519-x
    DOI: 10.1038/s41467-021-26519-x
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    References listed on IDEAS

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    1. David Sulzer & Roy N. Alcalay & Francesca Garretti & Lucien Cote & Ellen Kanter & Julian Agin-Liebes & Christopher Liong & Curtis McMurtrey & William H. Hildebrand & Xiaobo Mao & Valina L. Dawson & Te, 2017. "T cells from patients with Parkinson’s disease recognize α-synuclein peptides," Nature, Nature, vol. 546(7660), pages 656-661, June.
    2. Tony Wyss-Coray, 2016. "Ageing, neurodegeneration and brain rejuvenation," Nature, Nature, vol. 539(7628), pages 180-186, November.
    3. John V. Pluvinage & Michael S. Haney & Benjamin A. H. Smith & Jerry Sun & Tal Iram & Liana Bonanno & Lulin Li & Davis P. Lee & David W. Morgens & Andrew C. Yang & Steven R. Shuken & David Gate & Madel, 2019. "CD22 blockade restores homeostatic microglial phagocytosis in ageing brains," Nature, Nature, vol. 568(7751), pages 187-192, April.
    4. Cecilia S. Lindestam Arlehamn & Rekha Dhanwani & John Pham & Rebecca Kuan & April Frazier & Juliana Rezende Dutra & Elizabeth Phillips & Simon Mallal & Mario Roederer & Karen S. Marder & Amy W. Amara , 2020. "α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    5. Mohammad Shahnawaz & Abhisek Mukherjee & Sandra Pritzkow & Nicolas Mendez & Prakruti Rabadia & Xiangan Liu & Bo Hu & Ann Schmeichel & Wolfgang Singer & Gang Wu & Ah-Lim Tsai & Hamid Shirani & K. Peter, 2020. "Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy," Nature, Nature, vol. 578(7794), pages 273-277, February.
    6. David Sulzer & Roy N. Alcalay & Francesca Garretti & Lucien Cote & Ellen Kanter & Julian Agin-Liebes & Christopher Liong & Curtis McMurtrey & William H. Hildebrand & Xiaobo Mao & Valina L. Dawson & Te, 2017. "Erratum: T cells from patients with Parkinson’s disease recognize α-synuclein peptides," Nature, Nature, vol. 549(7671), pages 292-292, September.
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