New Cell Culture Model Identifies Potential ALS Drug Target
A novel cell culture model reveals new insights into the complex mechanisms underpinning neurodegeneration.
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Neurodegenerative disorders lack efficacious treatment
Researchers from the University of Zurich have created a novel neural cell culture model, called interconnected neuronal networks, or iNets.
The model enables the study of a protein called TDP-43, which is a common factor in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
A characteristic across neurodegenerative disorders is the death of nerve cells – or neurons – in different brain regions. In FTD, neurons in the frontal lobe and temporal lobe, brain areas that are important for cognition, language and personality, are affected. In ALS, there is progressive degeneration of neurons in the spinal cord and the motor cortex, resulting in paralysis.
Sadly, there are no efficacious treatments for FTD or ALS; pharmacological and other medical interventions currently target the symptoms, not the root cause, of neurodegeneration. Despite decades of research, the molecular and cellular mechanisms that steer both FTD and ALS are not well understood. The TDP-43 protein has been implicated, though, as roughly ~50% of FTD patients and the majority of ALS patients present with accumulation of the protein in their nervous system.
Developing a new cell model for neurodegeneration
The researchers sought a new way to study and replicate the behavior of TDP-43 in vitro. Led by Senior Scientist Dr. Marian Hruska-Plochan from the Department of Quantitative Biomedicine, they created iNets using human induced pluripotent stem cells (iPSCs).
“To explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors,” the authors described. “Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets).”
To create an effective cellular model of neurodegeneration, there are specific criteria that scientists must meet. The models must be reproducible, to ensure that experimental findings can be consistently and independently verified by other research groups. They must also have longevity so that the long-term study of gradual neurodegeneration and the processes involved is guaranteed.
iNets lasted exceptionally long periods of time, up to 12 months, and could be easily reproduced, the authors said. “The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise,” explained Hruska-Plochan. “And the flexibility of the model makes it suitable for a wide range of experimental methodologies.”
The “missing link” between aberrant TDP-43 behavior and neuronal cell death
Using iNets, Hruska-Plochan and colleagues identified a missing link between aberrant TDP-43 behavior and neuronal cell death: a toxic accumulation of NPTX2, a protein that is usually secreted through the synapses. TDP-43 controls the levels of NPTX2.
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“When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration,” the researchers said.
NPTX2 accumulation was also identified in post-mortem brain tissue from ALS and FTD patients. This validated the data produced using iNets and suggests that NPTX2 could be a potential drug target for ALS and FTD pathology.
“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, associate professor of biomedicine in the Department of Quantitative Biomedicine, and co-author of the study. “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 FTD in the future,” she concluded.
Reference: Hruska-Plochan M, Wiersma VI, Betz KM, et al. A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature. 2024. doi: 10.1038/s41586-024-07042-7
This article is a rework of a press release issued by the University of Zurich. Material has been edited for length and content.
