Unlocking the genetic secrets of Parkinson's disease through PARK gene research
For over two centuries, the cardinal motor symptoms that define Parkinson's disease have been recognized: the tremors, rigidity, and impaired movement. For fifty years, we've known these symptoms arise from the loss of dopamine-producing neurons in the brain. Yet a cure remains elusive. The turning point came in 1997, when scientists discovered tiny variations in a gene called alpha-synuclein could significantly increase Parkinson's risk. This breakthrough ignited a genetic "gold rush," revealing numerous other PARK genes that influence Parkinson's susceptibility 1 .
These PARK genes—numbered in the order of their discovery—account for only about 10-15% of Parkinson's cases, but they've opened unprecedented windows into the disease's molecular machinery.
Like finding specific words highlighted in a complex instruction manual, these genes direct researchers to the biological pathways most critical to understanding why neurons degenerate. The question is no longer just what these genes do, but whether we're fully appreciating the complete story they're telling us about Parkinson's multifaceted origins 2 .
Years since Parkinson's first described
Year of alpha-synuclein discovery
Cases linked to PARK genes
Forms Lewy bodies—dense protein clumps that are a pathological hallmark of Parkinson's. Both mutations and extra copies can cause Parkinson's 2 .
The most common genetic cause of late-onset Parkinson's in certain populations. Involved in multiple cellular processes 2 .
These three genes typically cause early-onset Parkinson's and work together in pathways that protect mitochondria from damage 2 .
Not technically numbered among the original PARK genes, but mutations represent one of the most significant genetic risk factors for Parkinson's 3 .
| Group | Inheritance | Typical Age of Onset | Key Genes | Primary Cellular Role |
|---|---|---|---|---|
| Group I | Autosomal Recessive | Early (teens-40s) | PARKIN, PINK1, DJ-1, ATP13A2 | Mitochondrial quality control, stress response |
| Group II | Autosomal Dominant | Middle to Late (35-65+) | SNCA, LRRK2, VPS35 | Protein processing, neuronal communication |
| Group III | Autosomal Recessive | Very Early (10-42) | DNAJC6, SJ1 | Synaptic vesicle recycling, neuronal development |
This grouping reveals a crucial insight: PARK genes are telling us that Parkinson's isn't a single disorder with one cause, but rather a convergence of multiple cellular dysfunctions that can lead to similar symptoms. The different ages of onset suggest some genes may impact brain development while others affect long-term maintenance 2 .
In March 2025, an international team of researchers at the Jan and Dan Duncan Neurological Research Institute published a breakthrough discovery in Cell Reports linking rare variants in a gene called ITSN1 to Parkinson's disease. The findings were striking: individuals carrying these rare ITSN1 variants faced up to a tenfold higher risk of developing Parkinson's compared to non-carriers 4 .
"We analyzed genetic data from nearly 500,000 UK Biobank participants and discovered that individuals carrying rare ITSN1 variants that impair the gene's normal function face up to a tenfold higher risk of developing Parkinson's disease."
ITSN1 Variants
Other PARK Genes
The team began by analyzing genetic data from approximately 500,000 participants in the UK Biobank, looking for rare genetic variants that occurred more frequently in people with Parkinson's disease 4 .
The initial findings were then validated across three independent cohorts comprising over 8,000 Parkinson's cases and 400,000 controls, ensuring the results weren't due to chance or population-specific factors 4 .
To understand how ITSN1 variants might cause problems, researchers turned to fruit fly models. They reduced ITSN1 levels in the flies and observed worsening of Parkinson's-like features, including impaired climbing ability 4 .
The team determined that ITSN1 plays an important role in synaptic transmission—how neurons communicate with each other. This makes it particularly relevant to Parkinson's, where disruption of nerve signals leads to characteristic symptoms 4 .
A tenfold increase in risk far exceeds that of many other known Parkinson's genes 4 .
ITSN1 represents a new pathway involved in how neurons communicate at synapses 4 .
Previous studies have linked similar ITSN1 mutations to autism spectrum disorder 4 .
| Aspect of Study | Description | Significance |
|---|---|---|
| Risk Increase | Up to 10-fold higher Parkinson's risk | Among the largest effect sizes for any Parkinson's gene |
| Validation | Confirmed in 3 independent cohorts (>8,000 cases, 400,000 controls) | High confidence in results across diverse populations |
| Biological Role | Regulates synaptic transmission | Links Parkinson's to neuronal communication pathways |
| Animal Model | Reducing ITSN1 in fruit flies worsened Parkinson's-like features | Supports causal role rather than mere association |
| Age of Onset | ITSN1 carriers trended toward earlier disease onset | May explain some early-onset cases |
Understanding PARK genes requires sophisticated tools and methods. Here are some key approaches and reagents that researchers use to decode the messages hidden in our DNA:
Allows comprehensive reading of genetic code to identify rare variants in large populations 3 .
Detects copy number variations (deletions/duplications) such as finding missing or extra sections in PARKIN gene 3 .
Measures molecular binding interactions for screening PARK7/DJ-1 inhibitors 5 .
Covalently binds to specific protein sites for selective inhibition of PARK7 active site 5 .
Creates patient-specific neurons for studying Parkinson's in human cells without brain tissue 2 .
Tests gene function in living organisms such as studying effects of reducing ITSN1 in fruit flies 4 .
Chemical probes like JYQ-88—a selective small-molecule inhibitor that covalently modifies the active site cysteine residue in PARK7/DJ-1—allow researchers to precisely manipulate and study this protein's function. Such tools "create new possibilities to explore PARK7 function in a physiologically relevant setting," as noted in a 2022 study 5 .
Meanwhile, multiple ligation-dependent probe amplification (MLPA) has proven crucial for detecting copy number variations that simpler sequencing methods might miss. As one study found, "MLPA revealed an additional 3 CNV in PARK2," highlighting the importance of using complementary methods for comprehensive genetic testing 3 .
Approaches targeting key aspects of Parkinson's pathogenesis identified through genetic research, including restoring dopamine systems and enhancing neuronal survival 6 .
Developing antibodies that target alpha-synuclein for clearance by the immune system. Several such therapies are currently in clinical trials 1 .
Targeting specific problematic proteins identified through genetic studies, such as the development of selective PARK7/DJ-1 inhibitors 5 .
To date, no single PD gene mutation has produced a perfect animal model that replicates all features of the human disease. This suggests either that Parkinson's is uniquely human or that the appropriate conditions haven't been replicated in animal models 2 .
PARK genes participate in interconnected networks, making it difficult to predict how modifying one might affect others. As one review noted, "A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation" 2 .
Future prospects may involve combinatory strategies targeting multiple pathways, such as multi-gene constructs delivered via high-capacity viral systems 6 .
More sophisticated stem cell-derived neurons and brain organoids that may better replicate human disease biology. These "are particularly valuable for elucidating human-specific cell biological functions" 2 .
Large-scale genetic studies in diverse populations will likely reveal additional genetic factors and help researchers understand how different genetic backgrounds influence Parkinson's risk and progression.
| Gene | Discovery | Potential Therapeutic Implications |
|---|---|---|
| ITSN1 | Rare variants increase risk 10-fold; affects synaptic function | New biological pathway for intervention; possible link between autism and Parkinson's 4 |
| SNCA & DRD2 | Identified as key genes linking Parkinson's and circadian rhythm disruptions | Explains sleep disturbances in PD; suggests timing of treatments |
| PARK7/DJ-1 | Development of selective inhibitor JYQ-88 | Tool compound for further research; potential therapeutic candidate 5 |
| GBA | Confirmed as most common genetic risk factor in European populations | Enzyme replacement therapies; small molecule chaperones 3 |
The conversation with our PARK genes is far from over. With each new discovery, we understand more about the complex orchestra of biological processes that maintain brain health—and what happens when they fall out of tune. The ITSN1 discovery reminds us that there are still major genetic contributors to be found, and that listening carefully to what these genes are telling us requires not just advanced technology, but creativity in interpreting the results.
As we continue this dialogue with our DNA, we move closer to a future where Parkinson's is not just manageable but preventable—where we can hear the whispers of risk genes before they become shouts of symptoms, and intervene while there's still time to make a difference.