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      Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson's disease.

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          Abstract

          Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer.

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          Targeting the NLRP3 inflammasome in inflammatory diseases

          Edward Olhava, Matthew S J Mangan, William Roush … (2018)
          Article 0 comments Cited 500 times – based on 0 reviews     Review now
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            The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy.

            Naonobu Fujita, Takashi Itoh, Hiroko Omori … (2008)
            Two ubiquitin-like molecules, Atg12 and LC3/Atg8, are involved in autophagosome biogenesis. Atg12 is conjugated to Atg5 and forms an approximately 800-kDa protein complex with Atg16L (referred to as Atg16L complex). LC3/Atg8 is conjugated to phosphatidylethanolamine and is associated with autophagosome formation, perhaps by enabling membrane elongation. Although the Atg16L complex is required for efficient LC3 lipidation, its role is unknown. Here, we show that overexpression of Atg12 or Atg16L inhibits autophagosome formation. Mechanistically, the site of LC3 lipidation is determined by the membrane localization of the Atg16L complex as well as the interaction of Atg12 with Atg3, the E2 enzyme for the LC3 lipidation process. Forced localization of Atg16L to the plasma membrane enabled ectopic LC3 lipidation at that site. We propose that the Atg16L complex is a new type of E3-like enzyme that functions as a scaffold for LC3 lipidation by dynamically localizing to the putative source membranes for autophagosome formation.
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              Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice

              Richard Gordon, Eduardo Albornoz, Daniel C Christie … (2018)
              Parkinson’s disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein–rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein–mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Mol Neurodegener
                Title: Molecular neurodegeneration
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 1750-1326
                ISSN (Print): 1750-1326
                Publication date (Electronic): August 16 2019
                Volume: 14
                Issue: 1
                Affiliations
                [1 ] Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, Michigan, 49503, USA. sonia.george@vai.org.
                [2 ] Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, Michigan, 49503, USA.
                [3 ] Laboratory of Neurodegenerative Diseases, Institut François Jacob, MIRCen, CEA, CNRS, 92265, Fontenay-aux-Roses, France.
                [4 ] Optical Imaging Core, Van Andel Research Institute, Grand Rapids, MI, USA.
                [5 ] Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI, USA.
                Article
                Publisher Item ID: 10.1186/s13024-019-0335-3
                DOI: 10.1186/s13024-019-0335-3
                PMC ID: 6697982
                PubMed ID: 31419995
                SO-VID: 44b80b18-64ad-430a-866d-1616c882e9f7
                History

                Keywords: Alpha-synuclein,Interleukin-4,Lipopolysaccharide,Microglia,Parkinson’s disease,Prion-like
                Data availability:
                Keywords: Alpha-synuclein, Interleukin-4, Lipopolysaccharide, Microglia, Parkinson’s disease, Prion-like

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