Genetic mutation linked to autism and other neurodegenerative diseases

by mcardinal

Lauren Dempsey, MS in Biomedicine and Law, RN, FISM News 


Researchers at Tel Aviv University say they have discovered genetic mutations that may be linked to autism, schizophrenia, and other neurodegenerative diseases like Alzheimer’s that could lead to a breakthrough in treatments for these conditions. The findings were published in a May issue of the “Molecular Psychiatry” journal.

The focus of the study was on how gene mutations cause brain damage and defects. 

Researchers obtained cells from patients with a rare syndrome called Activity-Dependent Neuroprotective Protein Syndrome (ADNP) or Helsmoortel-van der Aa Syndrome. This syndrome is caused by a mutation in the ADNP gene causing defects in the brain neurons and affects many body functions such as muscle tone, feeding, growth, hearing, vision, sleep, fine and gross motor skills, as well as multiple body systems including the immune system, heart, endocrine system, and gastrointestinal tract.

ADNP syndrome causes behavior disorders such as Autism Spectrum Disorder (ASD) and is thought to be one of the most common causes of non-inherited genetic autism. In the United States it is estimated that 1 in 27,000 people suffer from ADNP.

The study also focused on mutations of the SHANK3 gene which is responsible for providing instructions for making proteins found in the body’s tissues, especially the brain, playing an important role in the function of synapses and ensuring that signals are sent back and forth between neurons are received. 

By analyzing the mechanism that causes this specific genetic mutation in the ADNP and the SHANK3 genes, researchers were able to estimate that the abnormalities are at the root of thousands of autism cases around the world. Prof. Illana Gozes from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University said, “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 (though still extremely rare).”

However, when the genetic mutation occurs it can have various outcomes, with some forms causing more or less damage. Gozes explained that a section added to the protein provides protection and reduces damage by attaching to a control site of the neuron’s skeletal system, although a defective ADNP protein will result in a faulty skeleton causing impaired brain function. 

Researchers identified other sites on the ADNP protein that can bond with SHANK3 and similar proteins. One of which is located on NAP, which is part of the ADNP protein sequence, and is thought to control microtubules in neurons, but its exact purpose is not clear. Prevention of cell death and correction of mitochondrial dysfunction, however, have been identified as potential modes of action. 

Researchers took this information and developed an experimental drug, known as davunetide, and demonstrated that extended treatment with the drug improved the behavior of model animals with autism caused by SHANK3. The drug was also found to improve amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) in mouse models. The drug can be administered intranasally or intravenously. Davunetide has been tested in adults, proving to be safe and effective, however clinical trials in ADNP syndrome patients have not been carried out yet.  

Gozes remains optimistic about the team’s findings saying, “Better understanding of the gene mutations will lead to better disease management and more effective medication. Davunatide could be used to treat both autism and schizophrenia or a combination of them in the future, also protecting cognitive impairment in schizophrenia, currently a debilitating, unmet need.”