Article Impact Level: HIGH Data Quality: STRONG Summary of Cell Reports, 115355. https://doi.org/10.1016/j.celrep.2025.115355 Dr. Thomas P. Spargo et al.
Points
- The study identifies protein-truncating variants in the ITSN1 gene as a major genetic risk factor for Parkinson’s disease (PD), increasing the risk tenfold for carriers.
- By analyzing whole-genome sequencing data from over 8,407 PD cases and 413,432 controls, researchers confirmed a strong association between ITSN1 mutations and PD (combined p-value of 4.5 × 10⁻¹²).
- Drosophila models showed that loss of the ITSN1 ortholog, Dap160, worsened α-synuclein-induced neuronal toxicity and motor deficits, mirroring PD pathology.
- In vitro experiments confirmed a physical interaction between ITSN1 and α-synuclein, supporting the idea that synaptic vesicle trafficking dysfunction contributes to PD progression.
- ITSN1’s role in PD exceeds that of other known risk genes like LRRK2 and GBA1, and its link to autism spectrum disorder (ASD) suggests potential overlapping genetic pathways between neurodevelopmental and neurodegenerative diseases.
Summary
A recent study published in Cell Reports identifies protein-truncating variants in the ITSN1 gene as a significant risk factor for Parkinson’s disease (PD), revealing an approximately tenfold increased risk for carriers. By analyzing whole-genome sequencing data from 3,809 PD cases and 247,101 controls in the UK Biobank, the researchers found that individuals with rare ITSN1 mutations had an odds ratio (OR) of 10.5 (95% CI, 5.2–21.3) for developing PD (p = 6.1 × 10−7). This association was replicated in three additional cohorts, totaling 8,407 cases and 413,432 controls, with a p-value of 4.5 × 10−12. ITSN1’s role in PD was further supported by its known association with autism spectrum disorder (ASD), highlighting potential overlapping genetic pathways.
In vivo experiments using Drosophila models demonstrated that loss of the ITSN1 ortholog, Dap160, exacerbated α-synuclein-induced neuronal toxicity and motor deficits, mirroring the pathophysiological features of PD. In vitro assays further confirmed a physical interaction between ITSN1 and α-synuclein, reinforcing the involvement of synaptic vesicle trafficking dysfunction in PD progression. These findings suggest that ITSN1 plays a crucial role in synaptic transmission, a process pivotal to neuronal function and implicated in the neurodegeneration seen in PD.
This study positions ITSN1 as a major genetic contributor to PD, with an effect size surpassing other established risk genes like LRRK2 and GBA1. The discovery offers deeper insight into the genetic basis of PD and opens new avenues for therapeutic development. Additionally, the research suggests a potential link between PD and ASD, where individuals with ASD have a threefold higher risk of developing parkinsonism. These findings underscore the value of large-scale genetic studies in identifying rare mutations and potential therapeutic targets for PD.
Link to the article: https://www.cell.com/cell-reports/fulltext/S2211-1247(25)00126-3
References Spargo, T. P., Sands, C. F., Juan, I. R., Mitchell, J., Ravanmehr, V., Butts, J. C., De-Paula, R. B., Kim, Y., Hu, F., Wang, Q., Vitsios, D., Garg, M., Middleton, L., Tyrlik, M., Messa, M., Del Angel, G., Calame, D. G., Saade, H., Robak, L., … Dhindsa, R. S. (2025). Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease. Cell Reports, 115355. https://doi.org/10.1016/j.celrep.2025.115355
