AI Article Synopsis

  • Phelan-McDermid syndrome (PMDS) is caused by problems with a gene called SHANK3, which is found on chromosome 22 and is linked to autism.
  • Researchers studied patients with PMDS and found that not having enough SHANK3 causes brain cells to change too much, make more connections, and not work as well.
  • They tested thousands of small drugs and found one called Benproperine that can help fix some of these problems when given at the right time during brain cell growth.

Article Abstract

Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine's effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165012PMC
http://dx.doi.org/10.1038/s41398-024-02947-3DOI Listing

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