Summary: A new study has identified genetic variants in the ITSN1 gene that significantly increase the risk of developing Parkinson’s disease. Researchers analyzed nearly 500,000 genetic profiles and found that individuals carrying ITSN1 variants face up to a tenfold higher risk of Parkinson’s.
The study also linked ITSN1 to earlier disease onset and impaired neural signaling, crucial for movement and coordination. Experiments in fruit flies showed that reducing ITSN1 levels worsens Parkinson’s-like symptoms, supporting its role in disease progression.
Interestingly, similar mutations in ITSN1 have been associated with autism spectrum disorder, suggesting a potential link between ASD and Parkinson’s. These findings highlight ITSN1 as a promising target for future therapies.
Key Facts:
- Genetic Risk Factor: ITSN1 gene variants increase Parkinson’s risk up to tenfold.
- Neuronal Impact: ITSN1 plays a key role in synaptic transmission, affecting movement.
- ASD Connection: Similar mutations in ITSN1 have been linked to autism spectrum disorder.
Source: Baylor College of Medicine
A new study published in Cell Reports reveals a breakthrough discovery linking genetic variants in the gene ITSN1 to a significantly elevated risk of Parkinson’s disease, a neurodegenerative condition that affects nearly 2% of adults older than 65 years.
This work, led by an international team of researchers at Baylor College of Medicine, AstraZeneca and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, could pave the way for new treatments aimed at slowing or preventing Parkinson’s disease progression.
“Parkinson’s disease, the second most common neurodegenerative disorder, still has no cure.
“To tackle this unmet need, we analyzed genetic data from nearly 500,000 UK Biobank participants and discovered that individuals carrying rare ITSN1variants that impair the gene’s normal function face up to a tenfold higher risk of developing Parkinson’s disease,” said co-corresponding author Dr. Ryan S. Dhindsa, assistant professor of pathology and immunology at Baylor College of Medicine and principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.
These findings were subsequently validated across three independent cohorts comprising more than 8,000 cases and 400,000 controls. Importantly, ITSN1 carriers trended toward earlier age of disease onset.
“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.
“We focus on rare genetic mutations because they often confer large effects on disease risk that reveal critical disease mechanisms. These genetic discoveries not only deepen our understanding of Parkinson’s biology but also unveil promising new targets for therapeutic intervention,” Dhindsa explained.
ITSN1 plays an important role in how neurons send messages to each other – a process called synaptic transmission – making it particularly relevant to Parkinson’s disease, a condition in which disruption of nerve signals leads to the typical symptoms of impaired gait and balance, tremors and rigidity.
“We also showed in fruit flies that reducing ITSN1 levels worsens Parkinson’s-like features, including the ability to climb. We plan to extend these investigations to stem cell and mouse models,” Dhindsa said.
Interestingly, previous studies have recently implicated similar ITSN1 mutations in autism spectrum disorder (ASD). Other emerging data also have suggested an association between ASD and Parkinson’s disease, indicating that people with ASD are three times more likely to develop parkinsonism.
“Our findings support future studies to better understand the connections between these two conditions and the mechanisms involved,” Dhindsa said.
This study highlights ITSN1 as a promising therapeutic target and underscores the value of large-scale genetic sequencing in identifying rare mutations that contribute to complex neurological disorders.
Others contributors to this work include Thomas P. Spargo, Chloe F. Sands, Isabella R. Juan, Jonathan Mitchell, Vida Ravanmehr, Jessica C. Butts, Ruth B. De-Paula, Youngdoo Kim, Fengyuan Hu, Quanli Wang, Dimitrios Vitsios, Manik Garg, Lawrence Middleton, Michal Tyrlik, Mirko Messa, Guillermo del Angel, Daniel G. Calame, Hiba Saade, Laurie Robak, Ben Hollis, Vishnu A Cuddapah, Huda Y. Zoghbi, Joshua M. Shulman, Slavé Petrovski, Ismael Al-Ramahi and Ioanna Tachmazidou.
The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, AstraZeneca, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Rice University and the University of Melbourne.
About this genetics and Parkinson’s disease research news
Author: Graciela Gutierrez
Source: Baylor College of Medicine
Contact: Graciela Gutierrez – Baylor College of Medicine
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease” by Ryan S. Dhindsa et al. Cell Reports
Abstract
Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease
Despite its significant heritability, the genetic basis of Parkinson’s disease (PD) remains incompletely understood.
Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10−7; odds ratio [95% confidence interval] = 10.5 [5.2, 21.3]).
We replicate this association in three independent datasets totaling 8,407 cases and 413,432 controls (combined p = 4.5 × 10−12). Notably, ITSN1 haploinsufficiency has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity.
In Drosophila, we find that loss of the ITSN1 ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity and motor deficits, and in vitro assays further suggest a physical interaction between ITSN1 and α-synuclein.
These results firmly establish ITSN1 as a PD risk gene with an effect size exceeding previously established loci, implicate vesicular trafficking dysfunction in PD pathogenesis, and potentially open new avenues for therapeutic development.
