Recent research from the scientists at the University of Zurich and their collaborators elsewhere describes a neural cell culture model that sheds light on the mechanisms underlying neurodegeneration that occurs in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). They used the model to determine that neurons in both diseases express toxic levels of a protein called NPTX2, and to demonstrate how this particular protein could be a viable target for new therapies. 

Details of the study are published in Nature in a paper titled, “A model of human neural networks reveals NPTX2 pathology in ALS and FTLD.” The model, dubbed iNets, is derived from human induced pluripotent stem cells and features “synaptically connected and electrophysiologically active” neurons. According to the paper, iNets replicates the behavior of TDP-43, a protein that is overexpressed in neurodegenerative diseases including most ALS cases and about half of FTLD patients. The researchers also make a clear connection between “TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity” in both pathologies.

The model cultures can last up to a year and are easily reproduced making them ideal for studying the mechanisms of neuronal decline over time. “The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise,” said Marian Hruska-Plochan, PhD, a postdoctoral fellow in the department of quantitative biomedicine at the University of Zurich and first author on the paper. “And the flexibility of the model makes it suitable for a wide range of experimental methodologies.”

Using iNets, the scientists investigated the mechanisms of ALS and FTLD progression from initial TDP-43 protein dysfunction through to neurodegeneration. They hypothesized based on the model’s behavior that NPTX2 protein accumulation was the missing link between TDP-43 misbehavior and neuronal death. Validating that hypothesis required examining brain tissue samples from deceased ALS and FTLD patients to see if there were indeed higher levels of NPTX2 in cells containing abnormal TDP-43.

Their analysis confirmed the predicted relationship between the proteins and set the stage for the next set of experiments focused on assessing NPTX2 protein’s viability as a potential drug target for ALS and FTLD therapies. Essentially, the researchers engineered a setup where they lowered the levels of NPTX2 in neurons with TDP-43 overexpression. They found that keeping NPTX2 levels low successfully counteracted neurodegeneration in the iNets neurons. It is possible that drugs that work by targeting and reducing NPTX2 protein production could successfully halt neurodegeneration in ALS and FTLD patients.

Although these are promising predictions, it’s important to remember that the results are preliminary. “We still have a long way to go before we can bring this to the patients, but the discovery of NPTX2 gives us a clear shot of developing a therapeutic that acts at the core of the disease,” said Magdalini Polymenidou, PhD, an associate professor of biomedicine in the department of quantitative biomedicine at the University of Zurich and corresponding author on the paper. “In conjunction with two additional targets recently identified by other research teams, it is conceivable that anti-NPTX2 agents could emerge as a key component of combination therapies for ALS and FTLD in the future.

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