Gene mutation linked to substantial risk of Parkinson’s disease

Parkinson’s disease (PD) affects nearly 2% of adults over 65, making it the second most common neurodegenerative disorder. It leads to tremors, stiffness, slow movement, and balance issues due to the gradual loss of dopamine-producing neurons in the brain. While current treatments help manage symptoms, they cannot stop disease progression.

Researchers have long suspected that PD arises from a mix of genetic and environmental factors. Scientists now recognize that the disease involves disrupted cellular processes, including mitochondrial dysfunction, impaired protein degradation, and defective vesicle trafficking.

These disruptions contribute to the accumulation of misfolded α-synuclein proteins in brain cells, forming clumps called Lewy bodies. However, many of the genetic underpinnings of PD remain poorly understood.

A recent study, published in the journal Cell Reports, has shed light on a rare but powerful genetic contributor to PD risk. Using whole-genome sequencing (WGS) data from nearly 500,000 UK Biobank participants, researchers identified a strong link between mutations in the gene ITSN1 and an increased likelihood of developing Parkinson’s disease.

This discovery provides new insights into how genetic mutations affect PD progression and could pave the way for targeted therapies.

The study, conducted by an international team from Baylor College of Medicine, AstraZeneca, and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, found that individuals carrying rare, damaging ITSN1 variants face up to a tenfold higher risk of developing PD. These findings were confirmed in three independent cohorts totaling more than 8,000 PD cases and 400,000 control participants.

“What makes this discovery so significant is the exceptional magnitude of the effect of ITSN1 in increasing Parkinson’s risk, especially when compared with variants in other well-established genes such as LRRK2 and GBA1,” said Dr. Ryan S. Dhindsa, assistant professor at Baylor College of Medicine and principal investigator at the Jan and Dan Duncan Neurological Research Institute.

ITSN1 is crucial for synaptic transmission—the process by which neurons communicate. In PD, this communication breaks down, leading to motor symptoms such as tremors and rigidity.

The study’s authors conducted additional experiments in fruit flies and found that reducing ITSN1 levels worsened Parkinson’s-like symptoms, including impaired climbing ability. Future research will extend these investigations to stem cell and mouse models to explore the potential for therapeutic intervention.

This research highlights the importance of rare genetic mutations in understanding PD. Unlike common genetic variants that contribute small risks, rare mutations like those in ITSN1 can reveal critical disease mechanisms. Scientists believe these findings could guide the development of drugs targeting specific genetic pathways involved in neurodegeneration.

“We focus on rare genetic mutations because they often confer large effects on disease risk that reveal critical disease mechanisms. These genetic discoveries not only deepen our understanding of Parkinson's biology but also unveil promising new targets for therapeutic intervention,” Dhindsa explained.

One reason ITSN1 is particularly interesting is its role in vesicle trafficking, the process by which neurons package and transport signaling molecules. Previous research has linked disruptions in vesicle trafficking to PD, further supporting the importance of ITSN1 in disease progression. If future studies confirm that modifying ITSN1 activity can protect neurons, it could open new treatment avenues.

Interestingly, mutations in ITSN1 have also been implicated in autism spectrum disorder (ASD). Emerging research suggests individuals with ASD are three times more likely to develop parkinsonism later in life. The connection between these conditions is still unclear, but the latest study supports further investigation into shared genetic and molecular pathways.

“Our findings support future studies to better understand the connections between these two conditions and the mechanisms involved,” Dhindsa said.

The discovery underscores the power of large-scale genetic studies in unraveling the complexities of neurodegenerative diseases. By identifying key mutations with substantial effects, scientists move closer to understanding PD at its root cause.

While more research is needed to develop targeted treatments, this breakthrough provides a crucial step forward in combating Parkinson’s disease.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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