New cell culture model identifies potential ALS drug targets

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There are no effective treatments for neurodegenerative diseases

Researchers at the University of Zurich have created a new neuronal culture model called an interconnected neuronal network (iNet).

This model allows researchers to study a protein called TDP-43, which is a common factor in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

A hallmark of all neurodegenerative diseases is the death of nerve cells (or neurons) in various brain regions. In FTD, neurons in the frontal and temporal lobes are affected, which are brain areas important for cognition, language, and personality. ALS causes progressive degeneration of neurons in the spinal cord and motor cortex, resulting in paralysis.

Unfortunately, there are no effective treatments for FTD or ALS. Currently, pharmacological and other medical interventions target the symptoms rather than the underlying causes of neurodegeneration. Despite decades of research, the molecular and cellular mechanisms leading to both FTD and ALS are poorly understood. However, the TDP-43 protein is thought to be involved, as approximately 50% of FTD patients and the majority of ALS patients exhibit protein accumulation in the nervous system.

Development of new cellular models of neurodegeneration

Researchers sought new ways to study and reproduce TDP-43’s behavior. In vitro. Led by Marian Hruska-Procan, Ph.D., a senior scientist in the Department of Quantitative Biomedical Sciences, they created iNet using human induced pluripotent stem cells (iPSCs).

“To investigate the emergence and impact of TDP-43 pathology, we generated induced pluripotent stem cell-derived colony-morphological neural stem cells (iCoMoNSCs) by manual selection of neural progenitors,” the authors said. “Differentiated iCoMoNSCs formed a self-organizing multicellular system of synaptically connected and electrophysiologically active neurons that matured into a long-lived functional network, termed an iNet. .”

To create effective cellular models of neurodegeneration, there are certain criteria that scientists must meet. Models must be reproducible so that experimental results can be consistently and independently verified by other research groups. It must also have a long lifespan so that long-term studies of gradual neurodegeneration and associated processes are warranted.

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According to the authors, iNet persisted for a very long time, up to 12 months, and was easily reproducible. “The aging robustness of iNet allows us to perform experiments that would not otherwise be possible,” he explained Hruska-Plochan. “Also, the flexibility of the model makes it suitable for a wide range of experimental methods.”

The “missing link” between TDP-43’s abnormal behavior and neuronal cell death

Hruska-Plochan and colleagues used iNets to identify the missing link between aberrant TDP-43 behavior and neuronal cell death: toxic accumulation of NPTX2, a protein normally secreted through synapses. TDP-43 controls her NPTX2 levels.

“When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, but correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration,” researchers said.

NPTX2 accumulation was also confirmed in postmortem brain tissues of ALS and FTD patients. This validates the data generated using iNets and suggests that NPTX2 may be a potential drug target for his ALS and FTD pathology.

“While we still have a long way to go before we can make this available to patients, the discovery of NPTX2 provides a clear outlook for the development of treatments that target the core of the disease,” said Magdalini Polimenidou, Associate Professor of Biomedical Sciences. said. He holds a PhD in the Department of Quantitative Biomedical Sciences and is a co-author of this study. “Together with two additional targets recently identified by other research teams, we believe that anti-NPTX2 drugs may emerge as important components of combination therapy for ALS and FTD in the future,” she concluded. I attached it.

reference: Hruska-Plochan M, Wiersma VI, Betz KM, et al. Human neural network models reveal NPTX2 pathology in ALS and FTLD. Nature. 2024.doi: 10.1038/s41586-024-07042-7

This article is a re-edited version of a press release issued by the University of Zurich. Material has been edited for length and content.