Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration

Abstract

Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing; however, the precise mechanisms remain poorly understood. Herein, we report a neuroprotective role for microglia in the clearance of neuron-released α-synuclein. Neuronal α-synuclein activates microglia, which in turn engulf α-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy). Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-κB signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of α-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated synucleinphagy.

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

“…It is intriguing that besides standard UPS and autophagy, mTOR activation is bound to the replacement of standard-with immune-proteasome subunits, providing a possible link between concomitant autophagy and UPS alterations, bridging altered proteostasis with neuroinflammation ( Figure 2) [74]. Autophagy constitutively operates in neurons as well as astrocytes and microglial cells, where it is key to degrading phagocytosed Aβ or α-syn while restraining pro-inflammatory cytokine release, apoptosis, and neurotoxicity [220][221][222]. Inflammatory stimuli which are known to induce the immunoproteasome may impair autophagy activity within either glial cells or neurons.…”

Parkinson’s Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

“…Specifically, ANXA2 is recruited to the plasma membrane, during the formation of the phagocytic cup [56], and assists endosomes upon particle internalization by preventing destabilization [57]. Of note, several papers reported the involvement of ANXA2 in autophagy [58][59][60][61], a degradative process highly interconnected with the clearance of pathogens and aggregated proteins, including α-syn [62]. Indeed, multiple line of evidence indicates that AnxA2 knockdown or knock-out prevents endocytic transport beyond early endosomes, interferes with particle phagocytic transport and causes endosomal ultrastructural impairments [56,86,87].…”

“…Out of the mass spectrometry hits, found in two independent replicates, AnnexinA2 (human ANXA2) increased its affinity for LRRK2 upon α-syn PFF treatment. Intriguingly, ANXA2 is a phospholipid-binding protein that intervenes in phagocytic processes at multiple levels [56][57][58][59][60][61][62]. Specifically, it was reported that AnxA2 deficits are linked to a decreased endocytosis and particle internalization [56,63,64].…”

The Links between Parkinson’s Disease and Cancer

“…In PD, it is α-synuclein; in Alzheimer’s disease, these are neurofibrillary tangles (tauopathy—hyperphosphorylation inactivating the microtubule-stabilizing tau protein); and in Huntington’s disease, they are polyglutamine-containing proteins (polyQ-containing proteins). Recent research indicates the role of microglia and selective autophagy (synucleinphagy) in the removal of α-synuclein released by neurons [ 177 ]. According to experimental studies conducted on mice, neuronal α-synuclein activates microglia, which then absorb α-synuclein into autophagosomes.…”