A GROUNDBREAKING study has identified rare genetic variants in the ITSN1 gene that increase Parkinson’s disease risk by up to tenfold and reveal unexpected links to autism spectrum disorder (ASD), offering new pathways for therapeutic development.
Parkinson’s disease, a neurodegenerative condition affecting movement and cognitive function, has long been associated with genetic and environmental factors. Recent research highlights the critical role of synaptic transmission mechanisms in its progression. This international study, led by Baylor College of Medicine and Texas Children’s Hospital, analysed genetic data from nearly 500,000 individuals to uncover ITSN1’s dual association with Parkinson’s and ASD, challenging traditional understanding of these disorders’ distinct pathways.
The study analysed whole-genome sequences from 3,809 Parkinson’s patients and 247,101 controls in the UK Biobank, identifying rare protein-truncating ITSN1 variants as key risk factors (OR 10.5; 95% CI 5.2–21.3; p=6.1×10⁻⁷). Validation across three independent cohorts (8,407 cases, 413,432 controls) confirmed these findings (combined p=4.5×10⁻¹²). Carriers of ITSN1 mutations exhibited earlier disease onset, with fruit fly models showing worsened Parkinson’s-like symptoms—including impaired climbing ability—when ITSN1 levels were reduced. Mechanistically, ITSN1 interacts with α-synuclein, a protein central to Parkinson’s pathology, and disruptions in synaptic vesicle trafficking were implicated. Notably, ASD patients with ITSN1 variants were three times more likely to develop parkinsonism, suggesting shared biological pathways between the conditions.
These findings underscore ITSN1’s potential as a therapeutic target and advocate for genetic screening in high-risk populations. For clinical practice, integrating ITSN1 testing into diagnostic protocols could enable earlier interventions for Parkinson’s and ASD. Future research should prioritise developing therapies that restore ITSN1 function and clarify its role in synaptic communication. Additionally, longitudinal studies are needed to explore why ASD patients with ITSN1 variants face elevated Parkinson’s risk, potentially informing dual-diagnosis management strategies. The study’s emphasis on rare variants demonstrates how high-impact genetic discoveries can unveil disease mechanisms overlooked by conventional approaches.
Katrina Thornber, EMJ
Reference
Spargo TP et al. Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease. Cell Reports. 2025;DOI:10.1016/j.celrep.2025.115355.
