Researchers at Yale report in JCI Insight that the brain can mount a protective response to harmful rises in cellular calcium by increasing Glyoxalase 1 (GLO1). GLO1 helps clear toxic byproducts, and the team found higher GLO1 expression and activity in animals with excessive cellular calcium. This rise appears to compensate for calcium dysregulation, but the compensatory effect weakens with age when GLO1 activity falls.
The work, from laboratories led by Amy Arnsten and Lauren Hachmann Sansing, examined the ryanodine receptor 2 (RyR2), a calcium channel that releases calcium from the smooth endoplasmic reticulum. Elizabeth Woo, the first author, compared RyR2 to a faucet that can be turned on and off; when RyR2 is altered with age it can remain open and cause continuous calcium leakage. Prior studies link such RyR2 changes to Alzheimer’s disease and Long COVID.
Using an animal model with genetically altered RyR2 that stays "on," the team measured GLO1 expression and activity in the prefrontal cortex and hippocampus. GLO1 rose with age at first, peaking at 12 months in mice, then declined in older animals. Older animals that no longer maintained elevated GLO1 performed worse in a T-shaped maze, supporting the view that calcium dysfunction harms cognition and that GLO1 acts as a compensatory factor while active.
The authors suggest that understanding and sustaining this protective mechanism could guide new therapies that target GLO1 to prevent or slow neurodegeneration. The work received support from the National Institutes of Health and Yale University; the content is the responsibility of the authors and does not necessarily represent the NIH's official views.
Difficult words
- glyoxalase 1 — enzyme that helps clear toxic byproductsGLO1
- dysregulation — loss of normal control of a system
- ryanodine receptor 2 — cell protein channel that releases calciumRyR2
- compensate — make up for a loss or problem
- neurodegeneration — progressive loss of neurons and brain function
- expression — process of producing a protein from a gene
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Discussion questions
- What are the possible benefits and risks of developing therapies that increase or sustain GLO1 activity in older people?
- How might weakening compensatory mechanisms like the GLO1 rise affect everyday cognitive abilities?
- What kinds of evidence would you want to see before testing a GLO1-targeting therapy in humans?
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