New model identifies potential therapeutic target

Scientists from the University of Zurich have developed an innovative neural cell culture model, shedding light on the complex mechanisms underlying neurodegeneration. Their research identified a misbehaving protein as a promising therapeutic target in the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Their article is published in the journal Nature.

Neurodegenerative diseases cause the death of certain neurons in our brain, leading to different symptoms depending on the brain region affected. In amyotrophic lateral sclerosis (ALS), neurons in the motor cortex and spinal cord degenerate, leading to paralysis. In frontotemporal dementia (FTD), on the other hand, neurons located in parts of the brain involved in cognition, language and personality are affected.

Both ALS and FTD are progressive diseases and effective treatments are still lacking. As the population ages, the prevalence of age-related neurodegenerative diseases, such as ALS and FTD, is expected to increase.

Despite the identification of aberrant accumulation of a protein called TDP-43 in central nervous system neurons as a factor common to the vast majority of ALS patients and approximately half of FTD patients, the cellular mechanisms underlying The origin of neurodegeneration remains largely unknown.

Flexible, durable, reproducible: ideal cell culture model for ALS and FTD research

In their study, first author Marian Hruska-Plochan and corresponding author Magdalini Polymenidou from the Department of Quantitative Biomedicine at the University of Zurich developed a new neural cell culture model that reproduces the aberrant behavior of TDP-43 in neurons. Using this model, they discovered a toxic increase in NPTX2 protein, suggesting it as a potential therapeutic target for ALS and FTD.

To mimic neurodegeneration, Marian Hruska-Plochan developed a new cell culture model called “iNets,” derived from human-induced pluripotent stem cells. These cells, derived from skin cells and reprogrammed at a very early, undifferentiated stage in the laboratory, serve as a source for the development of many different and desired cell types. iNets are a network of interconnected neurons and their supporting cells growing in multiple layers on a plate.

The cultures lasted exceptionally long – up to a year – and were easy to reproduce. “The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise,” says Hruska-Plochan.

“And the flexibility of the model makes it suitable for a wide range of experimental methodologies.” As an example, iNets cell cultures provided the ideal model to study the progression of TDP-43 dysfunction to neurodegeneration.

How protein dysfunction leads to neurodegeneration

Using the iNets model, the researchers identified toxic accumulation of NPTX2, a protein normally secreted by neurons via synapses, as the missing link between TDP-43 misbehavior and neuronal death. To validate their hypothesis, they examined brain tissue from deceased ALS and FTD patients and indeed found that, also in patients, NPTX2 accumulated in cells containing abnormal TDP-43. This means that the iNets culture model accurately predicted the pathology of ALS and FTD patients.

In additional experiments in the iNets model, the researchers tested whether NPTX2 could be a target for drug design to treat ALS and FTD. The team designed a setup in which they lowered NPTX2 levels while neurons suffered from TDP-43 misbehavior.

They found that maintaining low levels of NPTX2 counteracted neurodegeneration in iNets neurons. Therefore, drugs that reduce the amount of NPTX2 protein could be a therapeutic strategy to halt neurodegeneration in patients with ALS and FTD.

Polyménidou sees great promise in this discovery. “We still have a long way to go before we can bring this to patients, but the discovery of NPTX2 gives us a clear chance to develop a treatment that works at the heart of the disease,” she said.

“In conjunction with two additional targets recently identified by other research teams, it is conceivable that anti-NPTX2 agents may emerge as a key component of combination therapies for ALS and FTD in the future,” he said. -she adds.