New insights into the mechanisms of “Niemann-Pick type C” in children

In the news”Scientific translational medicine“, scientists from DZNE and LMU Hospital report 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 are based on studies in mice Cell cultures and patients highlight that neuroinflammation, which is mediated by the brain’s immune system, plays a critical role in NPC. Furthermore, their research points to a biomarker that could potentially be useful in disease monitoring and assessment of response on the treatment This specifically concerns a molecule called TSPO, which can be detected in the brain by positron emission tomography (PET).

We usually associate dementia with the elderly. However, there are also forms of dementia that manifest in children and lead to death at the age of 30 or even earlier, such as Niemann-Pick type C.”

Dr. Sabina Tahirovic, neuroscientist at the DZNE site in Munich

It is estimated that approximately 150 people in Germany 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 cause movement disorders, as well as serious psychiatric and neurological symptoms, including dementia.

Biomarkers needed

“It often takes years for NPC to be diagnosed, with multiple visits to different doctors. The critical mutations are easy to detect, but NPC is often not initially considered because the disease is so rare,” explains Tahirovic. Certain drugs that act on lipid metabolism can relieve symptoms. However, so far there are no therapies that can permanently stop the disease. “Although we know the genetic causes of NPC, the mechanisms relevant to its development are still poorly understood. Our results now underline that neuroinflammation is a decisive factor in NPC. Furthermore, we have identified TSPO as a potential biomarker for disease monitoring and response to therapy,” says the neuroscientist “With the development of recent therapies 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 ‘microglia’: these cells belong to the brain’s immune system and are therefore specialized in fighting pathogens and other threats. However, in NPC they seem to do more harm than good. “We were able to show that the microglia actively contribute to NPC pathology by causing a damaging neuroinflammatory response in the brain,” says Tahirovic. “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 focus on reducing the amount of lipids in cells, because their overload is pathological “Our findings highlight the importance of inflammation in NPC. In view of this, I believe that combining lipid-lowering strategies with immunomodulation is a promising approach for future therapies.”

A potential biomarker

The current research combines studies in mice and cell cultures with the analysis of blood samples and PET scans from NPC patients. This was possible through a collaboration with the Department of Nuclear Medicine and the Department of Neurology of the LMU Hospital in Munich. “The so-called translocator protein, TSPO for short, is a common marker for inflammation in various brain diseases. However, until now, TSPO has not been associated with microglial activation and disease progression in NPC. Specifically, we found that microglial hyperactivity observed in NPC is reflected in a marked increase in TSPO levels. Because this molecule is found in the power plants of every cell, it apparently plays a role when microglial energy demand increases,” explains Tahirovic. “TSPO could thus serve as a marker for disease monitoring. That is, it could help evaluate the state of the disease and predict its further progression.” In addition, TSPO may also be useful for assessing the response to therapy. “We conclude this from data from patients who have been treated with a drug that can relieve the symptoms of NPC. This substance, called N-acetyl-L-Leucine, has recently been approved by the US authorities for the treatment of NPC,” says Tahirovic. “In my opinion, TSPO would be a valuable addition to the range of biomarkers currently used in other, more common neurodegenerative diseases. It would be useful to combine them and test their usefulness in clinical trials of NPC.”

PET and blood

TSPO can be imaged in the brain using PET scanning, a technique available in specialized clinics and molecular imaging facilities. “TSPO could be relevant for both clinical trials of NPC and clinical routine. PET imaging can be difficult in young patients, as they need to remain calm while in the scanner. But we have shown that it is feasible in older individuals affected by NPC,” says Prof. Matthias Brendel, a neuroimaging expert at LMU Hospital. In addition, data from current and previous studies suggest that certain blood cells reflect features of the microglia brothers and are sisters of the microglia.”Blood macrophages could also be a way to assess TSPO. Our current assays to monitor TSPO may still be too complex for clinical routine, but there is certainly room for development,” says Tahirovic. “Taken together, our findings not only shed new light on fundamental disease mechanisms, but can also provide practical have implications for NPC patients.”