Scientists have discovered that a mutation in the ITSN1 gene may increase the risk of developing Parkinson's. This gene helps transport substances within nerve cells, and its failure may contribute to the disease. Tests have confirmed this link, indicating that problems in this cellular transport may be one of the causes of Parkinson's, which could lead to new treatments in the future.
Parkinson's disease (PD) is a neurodegenerative condition that mainly affects older people and may have a hereditary origin.
It is characterized by motor symptoms, such as tremors at rest, muscle stiffness, slow movements (bradykinesia) and difficulties with walking and balance. In addition, some patients have loss of smell as an initial symptom.
Parkinson's disease is the second most common neurodegenerative disease, affecting between 1% and 2% of adults over the age of 65.
At the cellular level, Parkinson's disease is marked by the presence of abnormal structures called Lewy bodies, which are accumulations of the protein α-synuclein in brain cells. This protein aggregation occurs especially in the dopaminergic neurons of the substantia nigra, a brain region crucial for movement control.
The degeneration of these cells reduces the release of dopamine, a neurotransmitter essential for communication between neurons and motor control. With the decrease in dopamine, the brain circuits responsible for movement are affected, leading to the motor symptoms characteristic of the disease.
Currently, available treatments help alleviate symptoms, but cannot prevent the progression of neuronal loss.
Scientists believe that Parkinson's disease results from a combination of genetic and environmental factors. Genetic studies have identified mechanisms that contribute to the disease, such as problems in cellular energy production (mitochondrial dysfunction), failures in the protein recycling system (lysosomal dysfunction), difficulties in communication between neurons (synaptic dysfunction) and changes in the transport of vesicles within cells.
Initial research has focused on cases of inherited Parkinson’s disease, which accounts for about 5% to 10% of diagnoses.
Mutations have been identified in specific genes, such as SNCA (responsible for the production of α-synuclein), PRKN, GBA1 and LRRK2, which significantly increase the risk of developing the disease.
To better understand the genetic factors of Parkinson’s disease that are not inherited (sporadic cases), scientists use a technique called genome-wide association studies (GWAS). This approach analyzes genetic variations in thousands of people to identify regions of DNA associated with Parkinson’s disease.
However, interpreting these findings is challenging because many of these variations occur in parts of the DNA that do not code for proteins and have small effects.
In contrast, rare mutations that directly affect protein production may have a greater impact and provide clearer clues about the mechanisms of the disease and possible treatments. Despite advances, a significant part of the genetic contribution to Parkinson's disease is still unknown.
In the current study, researchers analyzed whole genome sequencing data from approximately 500,000 participants in the UK Biobank, a database that gathers genetic and health information from the UK population.
By examining this information, they identified a rare mutation that causes loss of function of the ITSN1 gene, which is responsible for producing a protein involved in the transport of vesicles within nerve cells. This discovery was made independently of another recent study that also suggested a link between ITSN1 and Parkinson's disease.
To confirm this finding, the scientists replicated the analysis in three other groups of patients with Parkinson's disease and people without the disease, totaling thousands of participants.
The results were consistent, strengthening the hypothesis that mutations in ITSN1 increase the risk of developing Parkinson's disease.
In addition, haploinsufficiency (when only one functional copy of the gene is not enough to maintain normal function) of ITSN1 has also been associated with autism spectrum disorder, suggesting that this mutation may influence different neurological conditions.
The researchers also conducted experiments in fruit flies (Drosophila), a model frequently used to study human diseases. They found that the absence of the gene corresponding to ITSN1 in these flies increased the toxicity of α-synuclein and worsened motor deficits.
In addition, tests in cultured cells showed that the ITSN1 protein can physically interact with α-synuclein, reinforcing the idea that dysfunction in vesicle transport contributes to the development of Parkinson's disease.
(A) An experiment in human cells (HEK293T) in which the scientists artificially produced the proteins ITSN1 and α-synuclein with a special tag (FLAG). They then used a method to pull down the ITSN1 protein and check whether α-synuclein was bound to it. The results confirmed this interaction and were repeated three times to ensure accuracy. (B–D) Microscope images showing the distribution of α-synuclein (red) and Dap160 (green) proteins in nerve connections (synapses) of fruit fly larvae. In the normal group (B), the organization of these proteins follows a typical pattern. In the groups that produce excess α-synuclein (C and D), the scientists observed spots where the two proteins overlapped (indicated by arrows). This suggests that α-synuclein may be interfering with the function of Dap160, a protein equivalent to ITSN1 in humans. The images analyzed come from 245 nerve connections from 18 modified larvae and 14 normal larvae.
This discovery is significant because the effect of this mutation in ITSN1 is stronger than other genetic variants previously identified for Parkinson's disease.
With this, the scientists not only confirm the importance of vesicular traffic in the progression of the disease, but also open up new possibilities for the development of treatments that can act on this specific mechanism.
Future research may explore how to correct this dysfunction and, possibly, create more effective therapies to prevent or slow the progression of Parkinson's disease.
Summary of the graphical scheme of all experiments performed.
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Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease
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 and Ryan S. Dhindsa,
Cell Reports. 7 March 2025
DOI: 10.1016/j.celrep.2025.115355
Abstract:
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.
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