A molecular brake on aging and multiple sclerosis discovered in mouse brains: the enzyme ENPP1, which neutralizes alarm signals from damaged cells

A molecular brake on aging and multiple sclerosis discovered in mouse brains: the enzyme ENPP1, which neutralizes alarm signals from damaged cells

On October 2, a preprint from Arc Institute and Stanford appeared on bioRxiv. The researchers showed in mice that aged and inflamed brain cells broadcast an alarm signal to one another, the molecule cGAMP, which triggers inflammation in neighboring cells; normally, the enzyme ENPP1 neutralizes this signal outside cells. Without this protection, the mice developed more severe autoimmune damage to the nervous system and signs of premature brain aging. The study reveals how the signal enters brain cells and identifies drug targets.

When excess DNA leaks from damaged mitochondria into the cytoplasm, the protein cGAS converts it into the signaling molecule cGAMP, which activates the protein STING and triggers inflammation, a response normally directed against viruses. Yet cGAMP also escapes from the cell and acts on its neighbors; this extracellular signal has long been studied by the laboratory of Stanford biochemist Lingyin Li, who demonstrated that cancer tumors use the same enzyme, ENPP1, to degrade cGAMP and hide from the immune system.

The authors tested which part of the central nervous system degrades cGAMP most actively and found the spinal cord, the primary site of damage in multiple sclerosis and its mouse model, EAE. During EAE, ENPP1 levels dropped in the mice while cGAMP and inflammation rose; the same decline in ENPP1 was found in postmortem tissue from people with progressive multiple sclerosis. To establish causality, the researchers engineered a mutation in ENPP1 that selectively eliminated its ability to degrade cGAMP; these mice experienced more severe EAE, and the effect was completely reversed when STING was also knocked out. A cGAS inhibitor administered after disease onset slowed paralysis. Even without EAE, the same mice with the ENPP1 mutation showed age-related deficits as early as four months: poorer balance, slower movement, and avoidance of open spaces; the effect was reversed when STING was knocked out.

The source of the signal is microglia, the immune cells of the brain: during EAE, mitochondrial DNA in their cytoplasm increases a hundredfold, and they release cGAMP into the extracellular space; in aged mice, cultured microglia secreted cGAMP at levels comparable to EAE, while young microglia did not. The receivers of the signal are microglia, astrocytes, and inhibitory neurons, with the strongest response in the neurons. This appears to be meaningful rather than incidental: a separate group has shown that inhibitory neurons activate STING signaling in multiple sclerosis while producing almost no cGAS, which suggests the signal arrives from outside, from microglia. Each cell type has its own entry route: microglia admit cGAMP through the ion channel LRRC8A:C, astrocytes take it in through an exchanger that swaps their glutamate (a neurotransmitter) for cGAMP, and neurons use the same mechanism, generating glutamate from glutamine themselves. Neuroinflammation is thus wired into the pumps that normally relay signals between neurons.

The discovery places ENPP1 in a dual role: in tumors it helps cancer evade the immune system, while in the brain it protects against inflammation and aging. The authors write:

We established that extracellular cGAMP is a central immunotransmitter of neuroinflammation that contributes to neurodegenerative disease and brain aging.

Two cGAS inhibitors have completed phase I and are being tested in phase II for autoimmune diseases, but they do not cross the blood-brain barrier, so brain-penetrant versions are needed. Boosting ENPP1 activity in the brain is the most direct practical implication of this finding.

The work comes from Arc Institute, a nonprofit research institute founded in 2021 with $650 million in capital so that scientists would not have to chase grants. The cGAS-STING pathway was discovered in 2013 as a defense against viruses; over the past 13 years it has become a foundational topic in cancer, autoimmune disease, and brain aging research.