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Background: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, abnormal accumulation of α-synuclein (α-syn), and microglial activation. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates multiple functions of microglia in the brain, and several studies have shown that TREM2 variant R47H is a risk factor for PD. However, the regulation of microglia by TREM2 in PD remains poorly understood., Methods: We constructed PD cell and animal models using α-syn preformed fibrils. siRNA knockdown and lentiviral overexpression were used to perturb TREM2 levels in cells, and TREM2 knockout mice and lentiviral overexpression was used in animal models to investigate the effects of TREM2 on microglial function, α-syn-related pathology, and dopaminergic neuron degeneration., Results: Microglia phagocytosed α-syn preformed fibrils in a concentration- and time-dependent manner, with some capacity to degrade α-syn aggregates. TREM2 expression increased in PD. In the context of PD, TREM2 knockout mice exhibited worsened pathological α-syn spread, decreased microglial reactivity, and increased loss of TH-positive neurons in the substantia nigra compared to wild-type mice. TREM2 overexpression enhanced reactive microglial aggregation towards the pathological site. Cellular experiments revealed that reduced TREM2 impaired microglial phagocytosis and proliferation, but enhanced autophagy via the PI3K/AKT/mTOR pathway., Conclusion: TREM2 signaling in PD maintains microglial phagocytosis, proliferation, and reactivity, stabilizing autophagy and proliferation via the PI3K/AKT/mTOR pathway. Regulating TREM2 levels may be beneficial in PD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Microglia are the main phagocytes in the brain and can induce neuroinflammation. Moreover, they are critical to alpha-synuclein (α-syn) aggregation and propagation. Plasma exosomes derived from patients diagnosed with Parkinson's disease (PD-exo) reportedly evoked α-syn aggregation and inflammation in microglia. In turn, microglia internalized and released exosomal α-syn, enhancing α-syn propagation. However, the specific mechanism through which PD-exo influences α-syn degradation remains unknown., Methods: Exosomes were extracted from the plasma of patients with PD by differential ultracentrifugation, analyzed using electron microscopy (EM) and nanoparticle flow cytometry, and stereotaxically injected into the unilateral striatum of the mice. Transmission EM was employed to visualize lysosomes and autophagosomes in BV2 cells, and lysosome pH was measured with LysoSensor Yellow/Blue DND-160. Cathepsin B and D, lysosomal-associated membrane protein 1 (LAMP1), ATP6V1G1, tumor susceptibility gene 101 protein, calnexin, α-syn, ionized calcium binding adaptor molecule 1, and NLR family pyrin domain containing 3 were evaluated using quantitative polymerase chain reaction or western blotting, and α-syn, LAMP1, and ATP6V1G1 were also observed by immunofluorescence. Small interfering ribonucleic acid against V1G1 was transfected into BV2 cells and primary microglia using Lipofectamine® 3000. A PD mouse model was established via injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into mice. A lentiviral-mediated strategy to overexpress ATP6V1G1 in the brain of MPTP-treated mice was employed. Motor coordination was assessed using rotarod and pole tests, and neurodegeneration in the mouse substantia nigra and striatum tissues was determined using immunofluorescence histochemical and western blotting of tyrosine hydroxylase., Results: PD-exo decreased the expression of V1G1, responsible for the acidification of intra- and extracellular milieu. This impairment of lysosomal acidification resulted in the accumulation of abnormally swollen lysosomes and decreased lysosomal enzyme activities, impairing lysosomal protein degradation and causing α-syn accumulation. Additionally, V1G1 overexpression conferred the mice neuroprotection during MPTP exposure., Conclusion: Pathogenic protein accumulation is a key feature of PD, and compromised V-type ATPase dysfunction might participate in PD pathogenesis. Moreover, V1G1 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which may provide opportunities to develop novel therapeutic interventions for PD treatment., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Circadian rhythms are involved in the regulation of many aspects of the body, including cell function, physical activity and disease. Circadian disturbance often predates the typical symptoms of neurodegenerative diseases and is not only a non-motor symptom, but also one of the causes of their occurrence and progression. Glial cells possess circadian clocks that regulate their function to maintain brain development and homeostasis. Emerging evidence suggests that the microglial circadian clock is involved in the regulation of many physiological processes, such as cytokine release, phagocytosis, and nutritional and metabolic support, and that disruption of the microglia clock may affect multiple aspects of Parkinson's disease, especially neuroinflammation and α-synuclein processes. Herein, we review recent advances in the circadian control of microglia function in health and disease, and discuss novel pharmacological interventions for microglial clocks in neurodegenerative disorders. • Circadian disturbance is not only a non-motor symptom, but also a vital risk factor for the occurrence and development of PD. • Circadian rhythm modulates microglia phagocytosis, metabolism and cytokine release under physiological conditions. • Microglia circadian disturbance affects oxidative stress, neuroinflammation, proteostasis and mitochondria dysfunction. • Circadian regulation is a potential direction for the treatment of neurodegenerative diseases and requires further research. [ABSTRACT FROM AUTHOR]