STING-dependent peripheral inflammaging drives neurodegeneration via extracellular vesicles

Area of Science:

• Gerontology
• Neuroscience
• Immunology

Background:

• Aging is a complex, heterogeneous process affecting different cells and organs at varying rates.
• Neurodegeneration, a key aging feature, often appears later than peripheral aging signs.
• Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2 GoF) are significant genetic risk factors for Parkinson's disease (PD).

Purpose of the Study:

• To investigate the role of LRRK2 GoF mutations in accelerated aging and Parkinson's disease.
• To elucidate the mechanisms linking peripheral inflammation to neurodegeneration in PD.
• To identify potential therapeutic strategies targeting inflammaging and neurodegeneration.

Main Methods:

• Analysis of Parkinson's disease patients and LRRK2 GoF mouse models.
• Investigating the role of STING-dependent inflammation in PD pathogenesis.
• Examining endolysosomal function, cytosolic self-DNA accumulation, and extracellular vesicle (EV) release.

Main Results:

• Parkinson's disease is characterized as an accelerated aging disorder driven by STING-dependent inflammation.
• LRRK2 GoF mutations lead to peripheral inflammation that disrupts the blood-brain barrier and causes dopaminergic neurodegeneration.
• Aging and LRRK2 GoF induce endolysosomal decline, promoting cytosolic self-DNA release via EVs, activating the cGAS-STING pathway.

Conclusions:

• LRRK2 GoF mutations accelerate aging and systemic inflammaging through DNA-containing EVs.
• The cGAS-STING pathway activation by self-DNA is a critical mechanism in LRRK2 GoF-driven neurodegeneration.
• Targeting DNA-containing EVs and the STING pathway may offer novel therapeutic avenues for Parkinson's disease and age-related inflammatory conditions.