Researchers have identified a cellular mechanism that may link a rare childhood disorder to Alzheimer’s disease. The study, conducted by scientists at the University of California, San Diego, and their colleagues, was published in the journal Immunity.
The researchers investigated Sanfilippo syndrome type A, a rare inherited disorder also known as mucopolysaccharidosis type IIIA (MPS IIIA). Children with the condition can develop seizures, dementia and other severe neurological problems, and their life expectancy is significantly reduced.
The disease is caused by a mutation in a gene responsible for producing the enzyme sulfamidase. Under normal conditions, this enzyme is involved in the function of lysosomes — structures inside cells that act as cellular recycling systems. Lysosomes break down nutrients, eliminate harmful substances and recycle damaged or worn-out cellular components.
When the enzyme is missing, cellular waste begins to accumulate.
Using mice with a model of Sanfilippo syndrome, the researchers found that microglia, the immune cells responsible for protecting the brain, are particularly affected. As fats and proteins accumulate, these cells become enlarged and gradually lose their ability to effectively protect neurons.
The scientists found that this process activates the MITF/TFE family of proteins, which function as genetic switches. When microglial lysosomes become overloaded and stressed, these proteins activate a program that is initially intended to help the cells cope with the damage.
However, under prolonged stress, the protective response can become harmful. Microglia begin to sustain inflammation, which can ultimately contribute to neuronal death.
One of the most significant findings was that the same genetic switches are activated in the microglia of people with Alzheimer’s disease. This suggests a possible connection between the mechanism that causes brain damage in the rare inherited disorder and processes involved in the much more common neurodegenerative disease.
The findings also offer a new perspective on how Alzheimer’s disease may develop. One widely discussed hypothesis is that amyloid plaques outside microglial cells disrupt lysosomal function and trigger cellular damage.
The new study suggests that the process could also work in the opposite direction: the initial source of damage may arise inside the brain’s immune cells themselves.
The researchers believe the MITF/TFE family could become a potential target for future drug development. In theory, controlling these genetic switches could help keep microglia in a protective state for longer and prevent them from shifting toward a chronic inflammatory and destructive state.
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