ITSN1 gene again linked to Parkinson’s risk in study
Rare mutations in gene found to raise risk by about 10 times
Rare mutations that impair the normal activity of the ITSN1 gene were found to increase the risk of Parkinson’s disease by about 10 times, according to a study.
The findings are in line with those of another recent study that linked ITSN1 mutations to an elevated Parkinson’s risk, particularly in those with an earlier age of disease onset.
The results “highlight ITSN1 as a potential therapeutic target” and underscore “the immense value of … efforts for identifying rare-variant contributions to complex diseases like PD [Parkinson’s disease],” the researchers wrote.
The study, “Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease,” was published in Cell Reports.
Parkinson’s is a neurodegenerative condition characterized by the progressive loss of nerve cells that produce the signaling chemical dopamine. Toxic accumulation of an abnormal version of the alpha-synuclein protein is implicated in this process.
What causes Parkinson’s is not completely understood, but the disease is thought to arise from a combination of genetic and environmental factors. A number of rare genetic variants, such as mutations in the SNCA or LRRK2 genes, have been strongly associated with familial forms of Parkinson’s.
Rare mutations offer clues
Genome-wide association studies, the approach commonly used to identify genetic contributors to sporadic Parkinson’s (cases in people with no family history of the disease) have pointed toward possible risk mutations. However, the genetic variants identified are usually common in the general population and fall in parts of genes that don’t directly code for protein production. It can be difficult to determine their actual significance in Parkinson’s.
The scientists believe it will be of value to identify more rare protein-coding mutations that have a clearer mechanistic link to Parkinson’s disease.
“We focus on rare genetic mutations because they often confer large effects on disease risk that reveal critical disease mechanisms,” senior author Ryan S. Dhindsa, MD, PhD, assistant professor at Baylor College of Medicine, said in a Baylor press release. “These genetic discoveries not only deepen our understanding of Parkinson’s biology but also unveil promising new targets for therapeutic intervention.”
The team analyzed genetic sequencing data from 3,809 Parkinson’s patients and 247,101 people without Parkinson’s, using data from the U.K. Biobank, a health research project that collects health information, genetic data, and lifestyle details from volunteers to help scientists study diseases.
ITSN1 emerged as one of the genes most closely linked to Parkinson’s.
People who carried protein-truncating mutations in ITSN1 were found to be at a 10 times greater risk for developing the disease.
Protein-truncating variants are ones that would lead to a shortened version of the gene’s protein product, which in this case, is Intersectin-1 (ITSN1). In many cases, cellular machinery will prevent the faulty protein from being produced, or if it is produced, it may be nonfunctional.
Ultimately, the researchers would classify these mutations as loss-of-function, meaning they impair the gene’s normal activity.
The mutations were rare, seen in nine of more than 3,000 Parkinson’s patients (0.24%) and 54 of more than 230,000 people without Parkinson’s (0.02%), but were strongly associated with the disease.
“What makes this discovery so significant is the exceptional magnitude of the effect of ITSN1 in increasing Parkinson’s risk, especially when compared with variants in other well-established, genes such as LRRK2 and GBA1,” Dhindsa said.
Additional research planned
The scientists replicated their findings across three other datasets cumulatively involving 8,407 Parkinson’s cases and 413,432 people without Parkinson’s.
Additional data suggested that Parkinson’s patients with ITSN1 mutations may be predisposed to an earlier disease onset.
These types of ITSN1 mutations have also been associated with autism spectrum disorder (ASD), and studies suggest that people with ASD are more likely to develop Parkinson’s-like symptoms.
“Our findings support future studies to better understand the connections between these two conditions and the mechanisms involved,” Dhindsa said.
In a fruit fly model, loss of the fly version of ITSN1 exacerbated motor deficits and the neurotoxic effects of alpha-synuclein. Alpha-synuclein and ITSN1 appeared to physically interact with each other in the flies.
“Collectively, these data establish ITSN1 as a genetic cause of PD and suggest that it may interact with [alpha-synuclein]-mediated pathogenic mechanisms,” the researchers wrote.
ITSN1 is important for protein interactions necessary for the proper trafficking of synaptic vesicles. These vesicles carry chemicals used to send signals between nerve cells at synapses, or the junctions through which nerve cells communicate.
While dysfunction of synaptic vesicle trafficking has been implicated in Parkinson’s, the researchers noted more studies are needed to clarify the precise role of ITSN1 in driving Parkinson’s.
Dhindsa said the team plans to do so by extending their investigations into stem cell and mouse models.
The research was conducted in collaboration with AstraZeneca, and 13 study authors are affiliated with the company.
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