The shared mechanism was discovered by mutations in various genes associated with autism, schizophrenia, and other conditions

summary: The researchers identified a mechanism shared by mutations in the SHANK3 and ADNP genes. Genes have been associated with the development of autism spectrum disorder and schizophrenia.

source: Tel Aviv University

Researchers at Tel Aviv University, led by Professor Ilana Joses from the Department of Human Molecular Genetics and Biochemistry at the Sackler School of Medicine and Sagol College of Neurosciences, have uncovered a common mechanism between mutations in the ADNP and SHANK3 genes, which cause autism, schizophrenia and other conditions.

The researchers also found that an experimental drug previously developed in Professor Jose’s lab is effective in laboratory models of these mutations and may be suitable for treating a group of rare syndromes that impair brain function.

According to the researchers, the encouraging results may lead to effective treatments for a group of rare syndromes that impair brain function and cause autism, schizophrenia, and neurodegenerative diseases such as Alzheimer’s.

Study participants: Dr. Yanina Ivashko Pachema, Maram Janaim, Inbar Ben-Horen Hazek, Alexandra Lubintseva, Naomi Belaich, Inbar Fischer, Gilad Levy, Dr. Shlomo Saragovich, d. The Sackler School of Medicine and Sagol College of Neurosciences at Tel Aviv University, Dr. Boaz Barak of the School of Psychological Sciences, Gershon H. Gordon School of Social Sciences and Sagol School of Neurosciences at the University of Washington, and Dr. Shula Chazman of the Department of Mathematics and Computer Science at the Open University.

The paper was published in the scientific journal Molecular Psychiatry.

Professor Joses: “Some cases of autism are caused by mutations in different genes. Today we know of more than 100 genetic syndromes associated with autism, 10 of which are considered relatively common (though still extremely rare).

“In our lab we focus primarily on one of these, ADNP syndrome, which is caused by mutations in the ADNP gene, which disrupt the function of the ADNP protein, leading to structural defects in the skeletal structure of neurons in the brain.

“In the current study, we identified a specific mechanism that causes this damage in mutations in two different genes: ADNP and SHANK3 – a gene associated with autism and schizophrenia. It is estimated that these two mutations are responsible for thousands of autism cases around the world.”

At first, the researchers obtained cells from patients with ADNP syndrome. They discovered that when the ADNP protein is defective, neurons with defective skeletons (microtubules) form, impairing brain function. They also found, however, that ADNP mutations take various forms, some of which cause less damage.

Professor Joses, who is also director of the Adams Super Center for Brain Studies at TAU, explains: “We discovered that in some mutants, an additive section protects them and reduces damage by contacting a control site in the neuron in the skeletal system. We know that this same control site It is present in SHANK3 – a much-studied protein that has mutations associated with autism and schizophrenia. We concluded that the ability to bind to SHANK3 and other similar proteins provides some protection against the harmful effects of the mutation.”

This indicates DNA
An experimental drug developed in a TAU laboratory may be suitable for treating a group of rare syndromes that impair brain function. The drug was found to be effective in animal models. The image is in the public domain

In the next phase of the study, the researchers found additional sites on the ADNP protein that could bind to SHANK3 and similar proteins. One of these sites is located in NAP, a division of ADNP developed into an experimental drug (Davunetide) by Professor Gozes’ laboratory.

Furthermore, the researchers showed that prolonged treatment with Davunetide significantly improved the behavior of autistic model animals induced by SHANK3.

Professor Joses: “In previous studies we have shown that Davunetide is effective in treating ADNP syndrome models. The new study led us to believe that it may also be effective in Phelan-McDermid syndrome, which is caused by a mutation in SHANK3, as well as other syndromes that cause autism through the same mechanism.

The Food and Drug Administration has recognized the experimental drug Davunetide as an orphan and rare pediatric drug for the future treatment of ADNP and is patent protected by Ramot, a technology transfer company at Tel Aviv University licensed exclusively to ATED Therapeutics Ltd.

ATED Therapeutics Ltd. (ATED)

ATED was formed around the work of Dr. Gozes by experienced business managers to develop Davunetide for clinical use. ATED is headed up by Dr. Jeff R. Soares as CEO, Joe Chiarelli as Chief Financial Officer, and Seasoned Medical Director for Clinical Trials, and Dr. Josep as Chief Scientific Officer.

ATED’s broad focus is on diseases of the central nervous system (CNS). Our initial target is a chronic and debilitating form of autism called ADNP (activity-dependent neuroprotective protein) syndrome that affects approximately 3,000-5,000 patients (ages 1-17) worldwide. The lead compound, Davunetide, is patented, safe, and non-toxic, and has been tested in over 300 adult patients. Since there is no cure for ADNP syndrome, it contains a rare pediatric and orphan drug from the Food and Drug Administration.

About this genetic research news

author: Nougat Shahar
source: Tel Aviv University
Contact: Noga Shahar – Tel Aviv University
picture: The image is in the public domain

original search: open access.
It binds the SH3, actin ADNP, and SHANK3-binding domains, revealing a common underlying mechanism of autismWritten by Yanina Ivashko-Pachema et al. Molecular Psychiatry

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It binds the SH3, actin ADNP, and SHANK3-binding domains, revealing a common underlying mechanism of autism

De novo heterozygous mutations in the neuronal activity-dependent protein (ADNP) cause the autistic ADNP syndrome. ADNP mutations impair the function of microtubules (MT), which are essential for synaptic activity.

The ADNP MT-binding fragment NAPVSIPQ (named NAP) contains the MT-end linker protein interaction domain, SxIP (mimicking active peptide, SKIP). We assumed it was not all ADNP Mutations are similarly harmful and that the NAPV portion of NAPVSIPQ is biologically active.

Using the eukaryotic linear stimulus resource (ELM), we identified the Src domain homology 3 (SH3) binding site in NAP that is responsible for controlling the signaling pathways regulating the cytoskeleton, that is, NAPVSIP.

Altogether, we mapped several SH3-binding sites in ADNP. Comparisons of the effects of ADNP mutations p.Glu830synfs*83, p.Lys408Valfs*31, p.Ser404* on MT dynamics and tau interactions (live cell microscopy) suggested that toxic function was spared in p.Lys408Valfs*31, with a restored SH3-binding motif. due to tire insertion.

Site-directed mutagenesis, which abrogates the p.Lys408Valfs*31 motif, binding SH3, produces MT toxicity. NAP normalized MT activities against all ADNP mutants, although SKIP, which lacked the SH3 binding motif, showed lower efficacy in terms of MT-Tau interactions, compared to NAP.

Finally, SH3 and several ankyrin domains protein 3 (SHANK3), a major autism gene product, interact with the cytoskeleton through the actin-binding motif to modulate behaviour.

Similarly, ELM analysis identified an actin binding site on ADNP, indicating direct SH3 association and indirect SHANK3/ADNP associations. Actin co-immunoprecipitation from mouse brain extracts showed NAP-mediated normalization of Shank3-Adnp-actin interactions.

Furthermore, NAP treatment improved the aberrant behavior in mice homozygous for Shank 3 The InsG3680 mutation, associated with ASD, reveals an underlying common mechanism between ADNP and SHANK3.