Clinical genetics

Zebrafish pinpoints culprit in rare brain disease ALSP

In people with the rare neurological disease ALSP, the white matter in the brain shrivels up, resulting in death. New research by Erasmus MC scientists shows what is going on: loss of microglia, the brain’s ‘cleaning cells.’

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Confocal laser scanner microscope image of a zebrafish brain. In green the white matter is visualized and in purple you can see the glia cells.

Less strength in arms and legs, behavioral changes, and memory problems. The symptoms of the brain disease ALSP – or adult-onset leukoencephalopathy – are similar to Alzheimer’s disease, dementia, or multiple sclerosis. The disease reveals itself around age 30 or 40 and leads in about half of the patients to death within five years.

Loss of cells called microglia in the brain is likely the culprit in ALSP. This was discovered by researchers from the Department of Clinical Genetics at Erasmus MC, led by associate professor Tjakko van Ham. The researchers describe their findings in Acta Neuropathologica.


Microglia and their branches are found in every millimeter of healthy brains. They are immune-like cells that constantly scavenge around the brain. They clean up debris and do other maintenance work on brain cells and neuronal connections. In the brain of patients with ALSP, there are noticeably fewer microglia present than in healthy brains. The researchers observed this in brain tissue from deceased patients.

Research by Ph.D. student Woutje Berdowski and analyst Herma van der Linde shows where this loss of microglia comes from. Using CRISPR/Cas9, they made zebrafish with exactly the same mutation as found in patients. It concerns a change in the gene CSF1R. The mutation leads to loss of microglia in the brains of the zebrafish avatars very early in development.


Exactly how this loss of microglia leads to white matter damage is not yet clear. ‘Possibly, the loss of microglia triggers a domino effect on other brain cells, eventually leading to the breakdown of white matter. If we understand this better, we can also learn more about other brain diseases in which microglia are involved,’ says Berdowski.

In Alzheimer’s disease, for example, microglia are thought to be the bad guys. ‘There is ongoing research on drugs called CSF1 inhibitors to temporarily reduce the number of microglia in Alzheimer’s patients. Our study shows that you have to be very careful with that,’ the Ph.D. student explains.


The researchers also saw another change. Another type of cell is suddenly more present in the brains of zebrafish with the CSF1R mutation. These were astrocytes, cells that can also clean up debris but are less good at it than microglia. The researchers also found evidence of increased activity of astrocytes in patients, although they could not study the early stage of the disease.

The astrocytes seem to compensate for the lack of microglia very early in the disease process. ‘That gets you thinking about whether the astrocytes can still perform their supportive brain functions properly when they are busy taking over tasks from the microglia,’ Berdowski says.

Stem cell transplantation

The discovery may also explain the success of stem cell transplantation as the only successful treatment for ALSP. A handful of patients have undergone stem cell transplantation which stabilized the disease. But how this worked is unknown. ‘We think that after transplantation, new microglia migrate from the bone marrow to the brain. There they probably replace the lost microglia,’ Van Ham says.

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