Discovery of a mechanism shared by mutations in different genes associated with autism, schizophrenia and other conditions – Neuroscience News

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Summary: Researchers have identified a common mechanism for mutations in the SHANK3 and ADNP genes. The genes have been linked to the development of ASD and schizophrenia.

Source: Tel Aviv University

Tel Aviv University researchers, led by Professor Illana Gozes of the Department of Human Molecular Genetics and Biochemistry at the Sackler School of Medicine and the Sagol School of Neuroscience, have discovered a mechanism shared by mutations in genes ADNP and SHANK3, which cause autism, schizophrenia and other conditions.

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

According to the researchers, the encouraging results could lead to effective treatments for a range of rare syndromes that impair brain function and cause autism, schizophrenia and neurodegenerative diseases like Alzheimer’s disease.

Study participants: Dr. Yanina Ivashko-Pachima, Maram Ganaiem, Inbar Ben-Horin-Hazak, Alexandra Lobyntseva, Naomi Bellaiche, Inbar Fischer, Gilad Levy, Dr. Shlomo Sragovich, Dr. Gidon Karmon, and Dr. Eliezer Giladi from the Faculty of Medicine Sackler and the Sagol School of Neuroscience at TAU, Dr. Boaz Barak from the School of Psychological Sciences, the Gershon H. Gordon School of Social Sciences and the Sagol School of Neuroscience at TAU, and Dr. Shula Shazman from the Department of Mathematics and Computer Science at the Open University.

The article was published in the scientific journal Molecular psychiatry.

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

“In our laboratory, we mainly focus on one of them, ADNP syndrome, caused by mutations in the ADNP gene, which disrupt the function of the ADNP protein, resulting in structural defects in the skeleton of neurons in the brain. .

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

To begin, the researchers obtained cells from patients with ADNP syndrome. They discovered that when the DNAP protein is defective, skeletally defective neurons (microtubules) form, impairing brain function. However, they also found that DNAP mutations take different forms, some of which cause less damage.

Professor Gozes, who is also director of the Adams Super Center for Brain Studies at TAU, explains: “We have found that in some mutations, a section added to the protein protects it and reduces damage by connecting to a control site of the neuron. skeletal system. We know that this same control site is on SHANK3 – a much-studied protein, with mutations associated with autism and schizophrenia. We concluded that the ability to bind SHANK3 and other similar proteins provides some protection against the harmful effects of the mutation.

An experimental drug being developed in a TAU lab could be suitable for treating a range of rare syndromes that impair brain function. The drug has been shown to be effective in animal models. Image is in public domain

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

Additionally, the researchers demonstrated that prolonged treatment with Davunetide significantly improved the behavior of model animals with autism caused by SHANK3.

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

The investigational drug Davunetide has been recognized by the FDA as an orphan and rare pediatric drug for the future treatment of ADNP development syndrome and is protected by patents through Ramot, the technology transfer company of the University of Tel Aviv and under exclusive license to ATED Therapeutics Ltd.

ATED Therapeutics Ltd. (ATED)

ATED was formed around Dr. Gozes’ work by experienced business leaders to develop Davunetide for clinical use. ATED is led by Dr. Jeff R. Swarz as CEO, Joe Chiarelli as Chief Financial Officer, an experienced Clinical Trials Medical Director, and Dr. Gozes as Chief Scientific Officer.

ATED focuses 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 which affects approximately 3,000-5,000 patients (ages 1-17) worldwide. The main compound, Davunetide, is patented, safe, non-toxic and has been tested on over 300 adult patients. Since there is no cure for ADNP syndrome, it has rare pediatric and orphan drug designation from the FDA.

About this genetic research news

Author: Noga Chahar
Source: Tel Aviv University
Contact: Noga Shahar – Tel Aviv University
Picture: Image is in public domain

Original research: Free access.
SH3 and actin binding domains link DNAP and SHANK3, revealing a shared fundamental mechanism underlying autism” by Yanina Ivashko-Pachima et al. Molecular psychiatry


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SH3 and actin binding domains link DNAP and SHANK3, revealing a shared fundamental mechanism underlying autism

De novo heterozygous mutations in activity-dependent neuroprotective protein (ADNP) cause autistic ADNP syndrome. ADNP mutations impair microtubule (MT) function, essential for synaptic activity.

The MT-associating DNAP fragment NAPVSIPQ (called NAP) contains a domain for interaction with the binding protein at the MT end, SxIP (mimicking the active peptide, SKIP). We hypothesized that all DNAP the mutations are also deleterious and that the NAPV part of NAPVSIPQ is biologically active.

Using the Eukaryotic Linear Motif (ELM) resource, we identified a Src homology domain-ligand association site 3 (SH3) in NAP responsible for controlling signaling pathways regulating the cytoskeleton, namely NAPVSIP.

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

Site-directed mutagenesis, abolishing the p.Lys408Valfs*31 SH3 binding motif, produced MT toxicity. NAP normalized MT activities against all DNAP mutations, although SKIP, lacking the SH3 binding motif, showed reduced efficacy in terms of MT-Tau interactions, compared to NAP.

Finally, SH3 and multi-domain ankyrin repeat protein 3 (SHANK3), a major autism gene product, interact with the cytoskeleton through an actin-binding motif to modify behavior.

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

In addition, NAP treatment ameliorated aberrant behavior in mice homozygous for the Stem3 ASD-linked InsG3680 mutation, revealing a fundamental mechanism shared between DNAP and SHANK3.

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