Scientists have identified a rare genetic mutation in ITSN1 that increases the risk of Parkinson’s disease by up to tenfold, marking one of the most significant genetic discoveries in the field.
This breakthrough, based on data from nearly 500,000 individuals, highlights how ITSN1 affects neural communication, potentially driving disease progression. Interestingly, similar mutations in ITSN1 have been linked to autism, further suggesting a connection between the two conditions.
A Genetic Breakthrough in Parkinson’s Disease
A new study published today (March 7) in Cell Reports has uncovered a major genetic link to Parkinson’s disease. Researchers identified variants in the ITSN1 gene that significantly increase the risk of developing the condition, which affects nearly 2% of adults over 65. Led by scientists from Baylor College of Medicine, AstraZeneca, and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, the study could help drive new treatments to slow or prevent 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.
Validation Across Large Populations
To confirm these findings, researchers validated the results across three independent groups, including over 8,000 Parkinson’s cases and 400,000 controls. They also found that individuals with ITSN1 variants tended to develop the disease at an earlier age.
“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.
The Role of ITSN1 in Brain Communication
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 have also 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.
A Path Toward Future Therapies
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.
Reference: “Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease” by 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 and Ryan S. Dhindsa, 7 March 2025, Cell Reports.
DOI: 10.1016/j.celrep.2025.115355
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.
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