Small glial cells "live swallow" alpha-synaptic nucleoproteins and degrade them by autophagy.

Click the blue word to pay attention to us. Alpha synuclein is a rich neuroprotein in the brain, which can maintain the normal function of synapses under normal conditions.neurodegenerative diseases such as Parkinson's disease (PD) and Lewy body dementia (DLB) have obvious α - synuclein aggregation.neurons secrete α - synuclein in the state of cell stress and injury.adjacent neurons and microglia can phagocytize and clear extracellular α - synuclein, and microglia have higher clearance efficiency, which helps to regulate the homeostasis of α - synuclein in the brain.most of the studies on the degradation of α - synuclein focus on neurons, and few studies on the degradation in microglia.on March 13, 2020, Professor Yue Zhenyu (Professor of Central South University and visiting professor of Huazhong University of science and Technology) of Friedman Institute of brain research, Mount Sinai, was in nature Articles published in the journal communications revealed that microglia play a protective role by scavenging α - synuclein secreted by neurons, suggesting that microglia may play an important role in the treatment of α - synuclein related diseases.the researchers injected AAV virus (AAV - α - SYN) into the substantia nigra compacta (SNC) of the midbrain, resulting in a decrease in the number of dopaminergic neurons and an increase in microglial activation.a large number of α - synuclein were found in microglia by immunofluorescence, which indicated that microglia could phagocytize α - synuclein.how these α - synuclein are degraded by microglia.autophagy is an important defense and protection mechanism.is there a possibility that the autophagy of microglia degrades these α - synuclein.previous studies have shown that p62 recognizes ubiquitination sites and interacts with them to initiate selective autophagy.after AAV - α - syn injection, p62 protein level increased, while other autophagy related receptors NDP52, optineurin and nbr1 did not change. These results indicate that the increase of α - synuclein can specifically cause the increase of p62 protein.immunofluorescence showed that p62, α - synuclein and LC3 were Co located in microglia, and autophagy structure was also found in microglia after injection of AAV - α - syn.these results suggest that α - synuclein in the "stomach" of microglia is degraded by autophagy.knockout of p62 also reduced the number of α - synuclein degraded by autophagy.further, immunoprecipitation showed that α - synuclein could interact with p62 directly. these results indicate that p62 binds directly to and recruits α - synuclein into autophagy. then how does microglia upregulate p62 when α - synuclein aggregates? Previous studies have shown that α - synuclein can activate TLR4 in cultured glial cells, resulting in increased transcription of inflammation related genes. the researchers used TLR4 knockout mice to conduct primary culture of microglia and found that p62 protein did not increase and autophagy related degradation was reduced even in the aggregation of α - synuclein. in addition, inhibition of TLR4 Signal also produced similar results, which indicated that the up regulation of p62 protein expression of α - synuclein was dependent on TLR4. the researchers further hybridized CX3CR1 CRE mice and Atg7 Flox mice to specifically knock out Atg7 (autophagy related protein 7) on microglia, which would hinder the autophagy function of microglia, but had no significant effect on the viability of microglia. after injection of AAV - α - syn, although p62 protein level was increased, it could not degrade α - synuclein well due to the dysfunction of autophagy after Atg7 knockout, which eventually led to the aggregation of α - synuclein. these results suggest that disruption of autophagy in microglia promotes the accumulation of misfolded α - synuclein and causes dopamine neuron death. in conclusion, we found that microglia clear α - synuclein and degrade α - synuclein through selective autophagy, thus playing a neuroprotective role. and further confirmed that TLR4 - p62 signaling pathway is involved in this process. References: 1. Microglia clear neuron released α - synuclein via selective autophagy and prevent neurogenesis