Cathepsin L-containing exosomes from α-synuclein-activated microglia induce neurotoxicity through the P2X7 receptor
Tianfang Jiang1, Chuanying Xu2, Shane Gao3
1Department of Neurology, Shanghai Eighth People's Hospital, 8 Caobao Road, Shanghai, China.
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.
Insights
Parkinson's disease involves microglia releasing Cathepsin L (CTSL) via exosomes, causing neuronal death. Inhibiting this exosome release pathway may offer new Parkinson's disease treatments.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Microglial activation is key in Parkinson's disease (PD) pathogenesis.
- Microglia secrete Cathepsin L (CTSL), impacting neuronal survival, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism of CTSL release from activated microglia in PD.
- To investigate the role of exosomes and signaling pathways in PD-related neurodegeneration.
Main Methods:
- Investigated CTSL release from alpha-synuclein (α-Syn)-activated microglia.
- Utilized exosome inhibitors (GW4869) and P2X7R/PI3K/AKT pathway antagonists.
- Assessed neuronal injury in cultured mouse cortical neurons.
Main Results:
- CTSL is primarily released via exosomes from α-Syn-activated microglia, causing neuronal damage.
- Exosome release mediated CTSL elevation, blocked by GW4869.
- The P2X7R/PI3K/AKT pathway is crucial; its inhibition reduced neuronal injury.
Conclusions:
- Exosomal CTSL release from activated microglia exacerbates neurotoxicity in Parkinson's disease.
- CTSL may represent a novel mechanism in PD pathogenesis.
- CTSL and its release pathway are potential therapeutic targets and biomarkers for PD.
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