Neurodegenerative diseases: New Insights into NPC

In the journal Science Translational Medicine, scientists from LMU Hospital and DZNE (Deutsches Zentrums für Neurodegenerative Erkrankungen) report on new insights into the mechanisms of “Niemann-Pick type C” (NPC), a rare neurodegenerative disease associated with dementia that can manifest as early as childhood.

Their findings, based on studies in mice, cell cultures and patients, emphasize that neuroinflammation, which is mediated by the brain’s immune system, plays a crucial role in NPC. In addition, their research points to a biomarker that could potentially be useful in disease monitoring and assessment of treatment response. Specifically, this refers to a molecule called TSPO, which can be detected in the brain by means of positron emission tomography (PET).

“We typically associate dementia with elderly people. However, there are also dementias that manifest in children and lead to death already by the age of 30 or even earlier, such as Niemann-Pick type C”, explains Dr. Sabina Tahirovic, a neuroscientist at DZNE’s Munich site. Besides her, Professor Matthias Brendel, expert in neuroimaging at LMU Hospital, is also significantly involved in the new study.

It is estimated that in Germany around 150 individuals are affected by this rare neurodegenerative disease. They have mutations in one of two specific genes that regulate lipid metabolism. This results in a harmful build-up of fat molecules in the brain and other organs. This, in turn, can trigger movement disorders as well as severe psychiatric and neurological symptoms, including dementia.

Inflammatory processes play a role

It is estimated that in Germany around 150 individuals are affected by this rare neurodegenerative disease. They have mutations in one of two specific genes that regulate lipid metabolism. This results in a harmful build-up of fat molecules in the brain and other organs. This, in turn, can trigger movement disorders as well as severe psychiatric and neurological symptoms, including dementia.

“It often takes years before NPC is diagnosed, with multiple visits to different doctors. The critical mutations are easy to detect, but NPC is often not considered initially because the disease is so rare”, Tahirovic explains. Certain drugs acting upon lipid metabolism can alleviate symptoms. However, so far, there are no therapies that can permanently halt the disease.

“Although we know the genetic causes of NPC, the mechanisms relevant for its development are still poorly understood. Our results now underscore that neuroinflammation is a decisive factor in NPC. Besides, we identified a potential biomarker for disease monitoring and response to therapy,” the neuroscientist says. “With the development of recent therapeutics for NPC, we urgently need such biomarkers to monitor clinical benefits and disease progression.”

A pathological cascade

Building on results from previous studies, Tahirovic and colleagues focused on the “microglia”: these cells belong to the brain’s immune system and are therefore specialized in combating pathogens and other threats. In NPC however, they seem to do more harm than good. “We were able to show that the microglia actively contribute to NPC pathology by triggering a harmful neuroinflammatory response in the brain”, Tahirovic says.

“Overall, we see these immune cells as part of a pathological cascade that also involves other brain cells and ultimately leads to neuronal damage. Current treatments for NPC aim to reduce the amount of lipids in cells, as their overload is pathological. Our findings not only shed new light on fundamental disease mechanisms, but may also have practical implications for NPC patients.”

Lina Dinkel et al.: Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease. Science Translational Medicine 2024