Extracellular Vesicles Link Inflammation in the Body to Accelerated Neurodegeneration in the Brain
STING is a master regulator of inflammatory signaling, triggered by a range of different sensor proteins for foreign material or forms of damage within a cell. With age, these sensors become overly active even in the absence of the usual stimuli, such as the presence of infectious agents, and the resulting inflammatory response is maladaptive, spreading harms further rather than helping the situation. Continual, unresolved inflammatory signaling is characteristic of old age, and it is disruptive to tissue structure and function. Here researchers note that inflammatory signaling in the body harms the brain via long-range communication between cells that is mediated via production and uptake of extracellular vesicles. Vesicles are small membrane-wrapped packages of molecules, carrying information from one cell to another. Their contents can change dramatically depending on the state of the originating cell, and this is one of the ways in which harms can spread, particularly in the context of chronic inflammation.
All animals age. However, aging is a heterogeneous process, and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same speed. For instance, neurodegeneration, a hallmark of aging, generally manifests later than other peripheral aging signs. The genetic determinants of aging are not completely understood.
Gain-of-function (GoF) mutations in leucine-rich repeat kinase 2 (LRRK2GoF) are major genetic risk factors for Parkinson's disease (PD). By analyzing PD patients and LRRK2GoF mice, we show that PD represents an accelerated aging disorder driven by STING-dependent inflammation. This inflammation begins peripherally, disrupts the blood-brain barrier, and causes dopaminergic neurodegeneration.
Mechanistically, aging or LRRK2GoF causes endolysosomal decline, resulting in cytosolic self-DNA accumulation and the release of DNA-containing extracellular vesicles (EVs) that activate the cGAS-STING pathway within and between cells. Our findings identify LRRK2GoF as a key driver of accelerated aging and systemic inflammaging through DNA-containing EVs, highlighting potential therapeutic targets to counteract inflammaging and neurodegeneration.