Synucleinphagy: a microglial “community cleanup program” for neuroprotection

Abstract

SNCA/α-synuclein is a major component in the Lewy body (LB), a pathological hallmark of Parkinson disease (PD) and dementia with Lewy body (DLB), collectively known as synucleinopathies. SNCA/α-synuclein can be secreted from neurons and transmitted to neighboring cells including neurons and glia, which underlie the spreading of LB pathology as described by Braak and colleagues. We recently have investigated the mechanism and significance for microglia, a prototypic phagocyte in the brain, in engulfing and controlling SNCA/α-synuclein homeostasis in the brain. Using microglia-specific autophagy-deficient mice, we demonstrated that microglia ingest and degrade neuron-released SNCA/α-synuclein through SQSTM1/p62-mediated selective autophagy both in vivo and in vitro. This process requires the presence of TLR4 (toll like receptor 4), which interacts with SNCA/α-synuclein to induce the transcriptional upregulation of Sqstm1/p62 through the NFKB/NF-κB pathway. We term the selective autophagy of SNCA/α-synuclein as “synucleinphagy”. We showed that the disruption of microglial autophagy causes accumulation of misfolded SNCA/α-synuclein and loss of dopaminergic neurons, two hallmarks of PD. Hence, our study reveals a neuroprotective role of microglia through an autophagy-mediated “community cleanup program”.