Researchers have identified a key cellular pathway driving brain degeneration in both a rare childhood disorder and Alzheimer’s disease, revealing how the brain’s immune cells respond to waste buildup. The findings, published in Immunity, could inform new therapeutic approaches for neurodegenerative conditions.
Scientists at the University of California San Diego studied a mouse model of Sanfilippo syndrome type A (MPS IIIA), a condition causing seizures and dementia in children due to a single gene variant that blocks production of the enzyme sulfamidase. Normally, cellular structures called lysosomes use this enzyme to break down nutrients, destroy harmful invaders, and recycle old cell components. Without it, debris accumulates.
The researchers found that whilst waste builds up in many cell types, microglia, the brain’s dedicated immune cells, are most severely affected. These cells expand as they become clogged with fats and proteins, losing their ability to protect neurons.
The team identified a family of proteins called MITF/TFE that act as master genetic switches. When lysosomes become overburdened, these switches are activated, triggering changes in the microglia’s genetic programme intended to protect the brain. However, this response eventually becomes maladaptive, fuelling inflammation and contributing to neuron death.
First author Dr Christopher Balak noted that whilst many researchers believe external amyloid plaques cause lysosomal failure, this study demonstrates that damage can originate directly within cells. The findings suggest early intervention before microglia become overwhelmed may be most effective for treating neurodegenerative diseases.
