CSF-1 receptor–related leukoencephalopathy (CRL) is a rare neurodegenerative disease leading to dementia and motor impairment caused by loss-of-function mutations in the CSF1R gene, which is crucial for the development and function of the brain’s immune cells known as microglia. Using a mouse model of CRL they developed, E. Richard Stanley, Ph.D., Violeta Chitu, Ph.D., and colleagues at Albert Einstein College of Medicine and elsewhere studied early changes in microglia before symptoms appeared.

As described in a study published February 26 in the Journal of Clinical Investigation, reduced signaling through the CSF-1 receptor disrupts how microglia regulate the distribution of essential metal ions such as zinc, copper, and iron in the brain. CRL microglia begin to abnormally accumulate and effectively “trap” these metals, depriving other brain cells, such as neurons and endothelial (blood vessel) cells, of the ions they need to function properly. This imbalance—marked by excess metal buildup in microglia and reduced availability to other cells—occurs on the background of decreased levels of metallothioneins, proteins that normally regulate metal distribution and protect cells from oxidative damage. Even presymptomatically, these changes trigger stress responses and early dysfunction in neurons, oligodendrocytes (cells that help insulate nerve fibers), and endothelial cells. Over time, these disruptions contribute to neurodegeneration. Importantly, restoring metallothionein levels in mice corrected metal imbalances, reduced cellular stress, and prevented behavioral symptoms. The findings suggest potential strategies for preventing CRL and possibly other neurodegenerative disorders.

Dr. Stanley is professor emeritus of developmental & molecular biology. Dr. Chitu, the first author, is a research professor of developmental & molecular biology.