跳转至内容
Merck
  • Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity.

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

Nature communications (2021-10-31)
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, Vania Broccoli
摘要

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.

材料
货号
品牌
产品描述

Sigma-Aldrich
1400W 二盐酸盐, >98%, solid