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”.

SNCA/α-突触核蛋白是路易体 (LB) 的主要成分，是帕金森病 (PD) 和路易体痴呆 (DLB) 的病理标志，统称为突触核蛋白病。SNCA/α-突触核蛋白可以从神经元分泌并传递到包括神经元和神经胶质在内的邻近细胞，这是 Braak 及其同事所描述的 LB 病理学扩散的基础。我们最近研究了小胶质细胞（大脑中的原型吞噬细胞）吞噬和控制大脑中 SNCA/α-突触核蛋白稳态的机制和意义。使用小胶质细胞特异性自噬缺陷小鼠，我们证明小胶质细胞通过 SQSTM1/p62 介导的体内和体外选择性自噬摄取和降解神经元释放的 SNCA/α-突触核蛋白。这个过程需要 TLR4（toll 样受体 4）的存在，Sqstm1 / p62通过NFKB / NF-κB 通路。我们将 SNCA/α-synuclein 的选择性自噬称为“synucleinphagy”。我们发现小胶质细胞自噬的破坏导致错误折叠的 SNCA/α-突触核蛋白的积累和多巴胺能神经元的丢失，这是 PD 的两个标志。因此，我们的研究通过自噬介导的“社区清理计划”揭示了小胶质细胞的神经保护作用。