October 8, 2024

An experimental Alzheimer’s drug provides new hopes to treat Autism

Critical roles of microRNAs in human health and disease are increasingly becoming clear. The 2024 Nobel prize in medicine, announced earlier this week, was awarded to this remarkable discovery. Adding new insights to this rapidly emerging field, a multi-institutional team led by Scintillon Institute and Scripps Research scientists reveals a key role for these tiny non-coding RNAs in Autism Spectrum Disorders. Using patient derived stem cell models, the team further discovers an aberrant neuronal activity in patient neurons, which the NMDA-receptor blocker Nitrosynapsin could at least partly rescue.

Autism Spectrum Disorders (ASD) is a neurodevelopmental disorder affecting millions of children worldwide. While there is wide variation in the type and severity of symptoms shown by these children, many exhibit impaired social communication, display of repetitive behaviors and intellectual disability. Despite the discovery of gene mutations and environmental factors contributing to ASD, we only have a limited understanding of the mechanisms underlying this debilitating disorder.

In a new multicenter collaborative study from the institute, the team probed into a form of ASD caused by mutations in MEF2C gene. To gain disease insights the team first generated induced pluripotent stem cells (iPSC) from skin punch obtained from autistic children carrying MEF2C mutations. These iPSCs were then coaxed to produce cerbrocortical neurons (the type that is most affected in ASD) and ‘mini-brains’ (a more physiologically relevant 3D cell model, also known as cerebral organoids, representing various brain cell types and interconnections). Upon examining these patient-specific models, the team noted early defects in the decision-making capacity of neural precursor cells to form neurons vs. glia. The basis for these defects could be traced to the low abundance of three microRNAs that are controlled by MEF2C. In normal brains MEF2C drives the production of these microRNAs to synergistically generate neurons by suppressing glial genes. Furthermore, more severe defects were noted when the patient cells matured into cerebrocortical neurons which produced neuronal networks that displayed hyperexcitation and an increased firing frequency.

“The most exciting aspect of our study is the discovery that Nitrosynapsin, a dual action compound related to the FDA approved drug memantine, can rescue the neuronal defects in our human patient samples, and that these results are consistent when tested in vivo in MEF2C mouse model that mimics the human disease. It opens new possibilities to repurpose this experimental Alzheimer’s drug for treating Autism patients”, said Dr. Rajesh Ambasudhan, an Associated Professor at the Scintillon’s Neurodegenerative Disease Center and an Associate Adjunct Professor at the department of Molecular Medicine at Scripps Research, who co-led the study along with Dr. Stuart Lipton, a Professor at the Neurodegeneration New Medicines Center at Scripps Research. “Given the involvement of MEF2C in controlling many ASD-related gene networks, our findings may have a wider implication on other forms of ASD as well”, Dr. Ambasudhan commented further.

The study was published in the journal Molecular Psychiatry and was online (https://doi.org/10.1038/s41380-024-02761-9) on September 30. The research was made possible by support from the US National Institutes of Health (NIH), California Institute of Regenerative Medicine (CIRM), and Autism Speaks.

Besides the study leaders Ambasudhan and Lipton, other scientists involved in the study are Dorit Trudler, Swagata Ghatak, Abdullah Sultan, James Parker, Sarah Moore Noveral, Mayu Teranaka, Nima Dolatabadi, Kevin Lopez, and Nobuki Nakanishi from Scintillon Institute, San Diego; Michael Bula, Maria Talantova, Melissa Luevanos, Sergio Labra, Titas Grabauskas, Emily Schahrer, Clare Bakker, and Parth Patel from Scripps Research, La Jolla; Agnes Chan, Yongwook Choi, Wei Lin, and Nicholas Schork from Translational Genomics Research Institute, Phoenix; Riki Kawaguchi and Daniel Geschwind from UCLA Medical School, Los Angeles; Pawel Stankiewicz from Baylor College of Medicine, Houston; Ivan Garcia-Bassets, Piotr Kozbial, and Michael Rosenfeld from HHMI, UCSD Medical School, La Jolla; and Shing Fai Chan from Sanford Burnham Prebys Medical Discovery Institute, La Jolla.