A long-overlooked part of the human genome appears to play a specific role in shaping the social and stereotypical repetitive behaviors that define autism spectrum disorder (ASD), without affecting learning or other cognitive abilities, according to a major new study. Nature.
A research team led by The Hospital for Sick Children (SickKids) has indicated that PTCHD1-ASA long non-coding RNA gene on the In particular, deletion withinPTCHD1-AS Affects social interactions and repetitive behaviors while affecting cognition.
While approximately 100 gene and copy number variations have been associated with ASD, most encode proteins and are associated with a wide range of developmental outcomes. These findings help to distinguish the biological mechanisms underlying the specific behavioral symptoms of autism from mechanisms involved in other brain functions.
” PTCHD1-ASThis gives us a new entry point to study the biology of ASD, increasing our understanding of how specific biological pathways relate to core autism symptoms. This is essential, because none of the new treatments in clinical trials are designed to modify the core features of ASD,” says senior author Dr. Stephen Shire, senior scientist, genetics and genome biology and head of research at SickKids and director of the McLaughlin Center at the University of Toronto.
a non-coding gene with a specific role
Approximately one in 50 children and youth in Canada has ASD. Despite the different ways of experiencing the condition, changes in social interactions and repetitive behaviors are common across the spectrum.
Long non-coding RNAs (lncRNAs), such as PTCHD1-AS regulate how other genes are turned on and off and have been largely unknown until recently. Researchers targeted PTCHD1-AS Because it sits in a region close to other protein-coding genes that have been simultaneously linked to ASD and intellectual disability.
Studying genomic data from more than 9,300 individuals in a global database, they found that dozens of X-linked deletionsPTCHD1‑AS Were associated with increased ASD susceptibility in males (females have a backup X chromosome).
Follow-up studies using mouse models developed by the research team further strengthened these findings. lack of male ratsPTCHD1-AS They only showed changes in social behavior and increased activity in repetitive tasks, while they behaved normally in learning, memory and attention tasks.
“Our findings suggest that there is a different biology involved with ourPTCHD1-ASmodel compared to other ASD protein-coding models,” says Dr. Lisa Bradley, first author and research associate in the Center for Applied Genomics (TCAG) at SickKids.
How PTCHD1-AS affects brain circuitry
What was going on in the minds of these rats? The team found it disruptivePTCHD1‑ASAffected “synaptic plasticity”, the brain’s ability to adapt and fine-tune signals in response to activity inside the striatum, where repetitive behavior is regulated.
“When we examined gene and protein expression in this region, we saw changes in genes and proteins involved in regulating synaptic plasticity as well as myelination, the process that allows electrical signals to travel rapidly between neurons. This gives us a molecular pattern that we can use for future studies into the biological impact of this non-coding gene in the brain,” says Bradley.
They traced these changes to reduced activity of protein kinase C in a specific brain circuit connecting the cortex to the striatum, as well as increased two forms of synaptic plasticity.
“Through a multidisciplinary approach combining human genetics, mouse models, multi-omics and electrophysiology, we have linked a non-coding gene to measurable changes in brain function,” said study co-author Dr. Graham Collingridge, senior investigator at Lunenfeld-Tannenbaum Research Institute, Mount Sinai Health and director of the Tanz Center for Research in Neurodegenerative Diseases and the university’s Temerty Faculty of Medicine. Professor in the Department of Physiology in Medicine says. Toronto.
“Together, our research helps to clarify how unique alterations in synaptic plasticity relate to core features of autism.”
Toward a more accurate understanding of ASD biology
The research team notes by linking a specific gene and biological pathway to social and repetitive behaviors, these findings may be relevant across all ASD diagnoses, regardless of clinical complexity.
Next steps in research include in-depth investigation of the pathways affected at the molecular, cellular, and circuit-levelPTCHD1-ASTo identify potential targets that drive core features of ASD and thereby inform future precision treatments for those who seek them.
Sherer, who is also a professor in the Department of Molecular Genetics at the Temerty Faculty of Medicine at the University of Toronto, says: “Beyond significantly advancing our understanding of autism as a human condition, the study shows how small changes in DNA can influence complex human behaviour.”
He says, “It’s amazing to me how much of our temperament is genetically ‘hardwired’, even in the traits that shape the way we connect and interact.”
