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Looking for the heart of lysosomal storage diseases

Graduate student Manuel Lopez, from the laboratory of developmental biologist and Howard Hughes Medical Institute investigator Matthew Scott, PhD, has published some interesting research (subscription required) in the Journal of Neuroscience about Niemann-Pick Type C disorder. Children with the heartbreaking condition, which is one of a class of inherited syndromes called lysosomal storage diseases, experience progressive, widespread neurological deterioration, losing motor and cognitive skills until their death, which typically occurs during the teen years. There is no effective cure or treatment other than supportive care.

The disease is primarily caused by a mutation in a gene encoding a protein called NPC1 that is responsible for helping cells transport and manage their stores of cholesterol. Without proper NPC1 function, cholesterol accumulates in all of the cells of the body, with devastating effects. The outcome is most dramatic in the nervous system, but it's not been clear whether neurons are specifically affected, or if other support cells such as astrocytes also contribute to the development of symptoms. Lopez recently told me:

Scientists tend to study the function of a normal brain, manipulating its circuitry to figure out what part of the brain elicits a specific neurological behavior. However, when studying a neurodegenerative disease, multiple brain areas are affected and whole networks may be working to compensate. That makes it difficult to know which brain regions are critical to save.

The researchers used a technique called selective gene therapy to replace the missing protein in various cell types in the brains of laboratory mice. They found that replacing the protein in the neurons, but not astrocytes, of mice with Niemann-Pick type C lessened symptoms and extended the animals' lifespan (although it didn't cure the disease entirely). The results are surprising because they finger neurons as the main culprit even though all the cells in the brain have the defect. The scientists conclude:

The advantage of using Niemann-Pick type C as a model to study neurological disorder comes from the cell autonomous effect of the disease and neuron specificity. That is, the lysosomal storage defect occurs only in the cell lacking NPC1 and the survival or death of a neuron is independent of the survival or death of neighboring neurons. This means scientists can explore the effects of maintaining specific neuronal circuitry in a disease that broadly affects the brain and causes multiple neurological behavioral problems.

What's next? The researchers are currently exploring ways to try and target more discreet neural networks in the brain and are also interested in testing if they can reverse the disease at late stages. In addition to Lopez and Scott, post-doc Andres Klein, PhD, and undergraduate student Ubah Dimbil also contributed to the work.

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