Summary: Researchers have identified rare genetic variants in the ITSN1 gene that markedly raise the risk of developing Parkinson’s disease. Analyzing nearly 500,000 genetic profiles, the team found that people who carry ITSN1 variants that reduce the gene’s function may face up to a tenfold increase in Parkinson’s risk.
The study also ties ITSN1 to earlier disease onset and to disruptions in neuronal signaling essential for movement and coordination. Experiments in fruit flies demonstrated that lowering ITSN1 levels worsens Parkinson’s-like motor defects, supporting a causal role for ITSN1 loss in disease progression.
Notably, similar ITSN1 mutations have been implicated in autism spectrum disorder (ASD), suggesting overlapping biological pathways between ASD and Parkinson’s. Together, these results nominate ITSN1 as a high-priority target for therapeutic research.
Key Facts:
- Genetic risk factor: Protein-truncating variants in ITSN1 are associated with a large increase in Parkinson’s risk—up to about tenfold in this analysis.
- Neuronal impact: ITSN1 is important for synaptic transmission, and loss of its function impairs neuronal signaling relevant to motor control.
- ASD connection: Related ITSN1 mutations have been reported in autism spectrum disorder, pointing to possible shared mechanisms across neurodevelopmental and neurodegenerative disorders.
Source: Baylor College of Medicine
New findings published in Cell Reports link loss-of-function variants in ITSN1 to a substantially increased risk of Parkinson’s disease, which affects roughly 2% of adults over 65.
An international team led by investigators at Baylor College of Medicine, AstraZeneca and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital analyzed whole-genome and exome data to search for rare variants that have large effects on Parkinson’s risk. Their primary analysis used nearly 500,000 participants from the UK Biobank and identified protein-truncating ITSN1 variants that strongly associate with Parkinson’s disease.
“To address an unmet need—Parkinson’s disease has no cure—we examined genetic data from nearly 500,000 UK Biobank participants and found that rare ITSN1 variants impairing gene function were associated with up to a tenfold increase in Parkinson’s risk,” said Dr. Ryan S. Dhindsa, co-corresponding author and assistant professor of pathology and immunology at Baylor College of Medicine, who is also principal investigator at the Jan and Dan Duncan Neurological Research Institute.
The association was validated across three independent cohorts totaling more than 8,400 Parkinson’s cases and 413,000 controls, strengthening the evidence that ITSN1 haploinsufficiency elevates disease risk. Carriers of damaging ITSN1 variants also tended to develop symptoms at an earlier age.
Dhindsa emphasized the importance of studying rare variants: “Rare mutations often have large effects and can reveal critical mechanisms underlying disease. Discoveries like this both deepen our understanding of Parkinson’s biology and point to new targets for intervention.”
ITSN1 encodes a protein involved in synaptic vesicle trafficking and synaptic transmission—the processes by which neurons communicate. Disruption of these processes is central to Parkinson’s pathology, which manifests clinically as tremor, rigidity, and impaired gait and balance.
Functional studies further support the genetic findings. In Drosophila, reducing expression of the ITSN1 ortholog Dap160 aggravated α-synuclein–induced neuronal toxicity and produced motor deficits such as impaired climbing. In vitro assays also suggest a physical interaction between ITSN1 and α-synuclein, linking ITSN1 dysfunction to known molecular pathways in Parkinson’s disease.
Previous reports have associated ITSN1 haploinsufficiency with autism spectrum disorder, and other epidemiological data indicate a greater-than-expected occurrence of parkinsonism among people with ASD. The authors note that variable penetrance and expressivity may help explain how similar ITSN1 variants can contribute to different clinical outcomes.
This body of work positions ITSN1 among the most impactful genetic risk factors identified to date for Parkinson’s disease, exceeding the effect sizes observed for many previously known risk genes. By implicating vesicular trafficking and synaptic dysfunction, the study opens potential directions for therapeutic development aimed at stabilizing neuronal signaling or compensating for ITSN1 loss.
Contributors to the study 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.
Affiliated institutions include 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: Image credit: 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. DOI: 10.1016/j.celrep.2025.115355
Abstract
Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease
Parkinson’s disease has substantial heritability, but many genetic contributors remain undiscovered. By analyzing whole-genome sequence data from 3,809 Parkinson’s cases and 247,101 controls in the UK Biobank, the investigators identified protein-truncating variants in ITSN1 that confer a markedly increased risk of Parkinson’s (p = 6.1 × 10−7; odds ratio = 10.5 [95% CI 5.2–21.3]).
The association was replicated in three independent datasets totaling 8,407 cases and 413,432 controls (combined p = 4.5 × 10−12). ITSN1 haploinsufficiency has also been linked to autism spectrum disorder, indicating variable penetrance and expressivity across clinical presentations.
In Drosophila, loss of the ITSN1 ortholog Dap160 intensified α-synuclein–driven neuronal toxicity and motor deficits, while in vitro experiments suggest a physical interaction between ITSN1 and α-synuclein. These results establish ITSN1 as a Parkinson’s risk gene with an effect size larger than many previously established loci, implicating vesicular trafficking dysfunction in Parkinson’s pathogenesis and identifying a promising avenue for therapeutic exploration.