Cracking the code of neurodegeneration: New model identifies potential therapeutic target

Neurodegenerative diseases cause some neurons in our brain to die, resulting in different symptoms depending on the affected area of ​​the brain. 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 in parts of the brain involved in cognition, language and personality are affected.

Both ALS and FTD are continuously evolving 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 abnormal accumulation of a protein called TDP-43 in neurons of the central nervous system as a common factor in the majority of ALS and about half of FTD patients, the underlying cellular mechanisms driving neurodegeneration remain largely unknown.

Flexible, sustainable, reproducible: ideal cell culture models for ALS and FTD research

In their study, first author Marianne Hrska-Plochin and corresponding author Magdaleni Polimenido of the Department of Quantitative Biomedicine at the University of Zurich developed a new neural cell culture model that mimics the abnormal behavior of TDP-43 in neurons. Using this model, they discovered a toxic increase in the protein NPTX2, suggesting it as a potential therapeutic target for ALS and FTD.

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

Cultures lasted unusually long—up to a year—and reproduced easily. “The robustness of aging iNets allows us to do experiments that wouldn’t have been possible otherwise,” says Hruska-Plochan. “And the model’s flexibility makes it suitable for a wide range of experimental approaches.” As an example, iNets cell cultures provided the ideal model for investigating the progression from TDP-43 dysfunction to neurodegeneration.

How protein misfolding leads to neurodegeneration.

Using the iNets model, the researchers identified toxic accumulation of NPTX2, a protein normally secreted by neurons at 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 NPTX2 accumulated in cells with abnormal TDP-43 even in the patients. 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 developed a setup in which they reduced NPTX2 levels while neurons were misbehaving with TDP-43. They found that keeping NPTX2 levels low counteracted neurodegeneration in iNets neurons. Therefore, drugs that reduce the amount of the protein NPTX2 have potential as a therapeutic strategy to prevent neurodegeneration in patients with ALS and FTD.

Magdalini Polymenidou sees great promise in this discovery: “We still have a long way to go before we can bring it to patients, but the discovery of NPTX2 gives us a clear shot at developing a treatment that can treat the disease. works on the basis,” she said. “Combined 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.”