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., Hollis, B., Cuddapah, V.A., Zoghbi, H.Y., Shulman, J.M., Petrovski, S., Al-Ramahi, I., Tachmazidou, I., Dhindsa, R.S. (2025). Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson's disease.  Cell Rep. 44(3): 115355.

FBrf0261987

Research paper

Despite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10[-7]; odds ratio [95% confidence interval] = 10.5 [5.2, 21.3]). We replicate this association in three independent datasets totaling 8,407 cases and 413,432 controls (combined p = 4.5 × 10[-12]). Notably, ITSN1 haploinsufficiency has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, we find that loss of the ITSN1 ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity and motor deficits, and in vitro assays further suggest a physical interaction between ITSN1 and α-synuclein. These results firmly establish ITSN1 as a PD risk gene with an effect size exceeding previously established loci, implicate vesicular trafficking dysfunction in PD pathogenesis, and potentially open new avenues for therapeutic development.

PMC12124131 (PMC) (EuropePMC)