Cathepsin L-containing exosomes from α-synuclein-activated microglia induce neurotoxicity through the P2X7 receptor

Abstract

Uncontrolled microglial activation is pivotal to the pathogenesis of Parkinson’s disease (PD), which can secrete Cathepsin L (CTSL) to affect the survival of neurons in the PD patients; however, the precise mechanism has yet to be determined. We demonstrated for the first time that CTSL was mostly released by exosomes derived from α-Syn-activated microglia, resulting in neuronal damage and death. The elevation of CTSL activity was blocked by GW4869, suggesting a critical role for exosomes in mediating CTSL release. Furthermore, the P2X7R/PI3K/AKT signalling pathway was identified as the underlying molecular mechanism since specific antagonists of this signalling pathway, P2X7R knockdown and exosome release inhibitors significantly reduced the injury to cultured mouse cortical neurons. Our study suggests that increased extracellular release of CTSL from α-Syn-activated microglia through exosomes amplifies and aggravates of the neurotoxic effect of microglia, implying that CTSL may be involved in a fresh mechanism of PD pathogenesis, and serve as a potential biomarker and a target for PD drug development.

Microglia activation in central nervous system disorders: A review of recent mechanistic investigations and development efforts

“…Xia et al found that microglia exosomes are involved in the α-Sny aggregation in the pathological process ( 119 ). Activated microglia releases exosomes that promote the infection of insoluble α-Sny with normal cells and propagate the aggregation of pathological α-Sny, which is accelerated by pro-inflammatory factors released in response to microglia inflammation, and the use of GW4869 (an inhibitor of sphingosine phosphodiesterase) significantly reduces the number of exosomes and decreases α -Sny proliferation and aggregation, leading to the possibility of targeting microglia exosomes for PD treatment ( 120 ). Also, age-related changes in the inflammatory response, as well as genetic and environmental factors, may contribute to the prevalence of pro-inflammatory microglia and affect the susceptibility to microglia activation, which may further influence the pathogenesis and lead to progressive neuronal loss.…”

Exploring [11C]CPPC as a CSF1R-targeted PET Imaging Marker for Early Parkinson’s Disease Severity

“…While this study cannot establish a causal link between microglial activation and α-synuclein-related neurodegeneration, it aligns with preclinical and neuropathological evidence that supports a contributory role in cell death. Microgliosis precedes cell death in α-synuclein over-expression animal models (28) and in human autopsy studies(23) and at least two mechanisms have been proposed: 1) direct or indirect (via activation of neurotoxic astrocytes) toxicity to neurons by α-synuclein-activated microglia (1, 23, 29) and 2) microglia-mediated enhancement of α-synuclein oligomerization(30) and spread throughout the brain(31, 32). Since some of the most promising disease-modifying agents in PD(33) are thought to act via microglia(7), having an in vivo biomarker for microglial activity may facilitate therapy development and hasten drug trials as an indicator of target engagement in proof-of-principle studies and clinical trials.…”

LncTCONS_00058568 is involved in the pathophysiologic processes mediated by P2X7R in the lower thoracic spinal cord after acute kidney injury

“…Previous studies have demonstrated that the activation of P2X7R in microglia triggers inflammatory intracellular signaling via the PI3K/Akt signaling and NF-κB signaling pathways, 26,27 combined with RNA-seq data. We used qRT-PCR and WB analysis to confirm these pathways.…”