ITSN1 gene linked to substantial risk of Parkinson’s disease

(Press-News.org) HOUSTON – (March 7, 2025) – 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.

For the complete list of support sources for this work, see the publication.

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