
Research by Weill Cornell Medicine has led to the development of a new model for understanding Parkinson’s disease progression and offers an innovative method for early detection of the condition. The findings, published today in Nature Communications, could ultimately lead to better management strategies and improved outcomes for those affected by the disease.
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. It has been diagnosed in roughly 500,000 people in the U.S., but experts in the field believe there is about an equal number of people suffering from Parkinson’s who haven’t been diagnosed. In its later stages, patients show motor symptoms such as tremors and stiffness and other non-motor issues including vision problems, cognitive decline, and sleep disturbances. Because of the disease’s complex pathology, detecting and studying the early stages of the disease is challenging.
The Weill Cornell team believes their work can help researchers better understand the earlier stages of the disease. Their new mouse model mimics the progression of Parkinson’s disease in humans more closely than previous models. “This is a really unique model involving a pathology that seems more like human Parkinson’s than what we see in other mouse models,” said Ching-Hwa Sung, PhD, a professor in stem cell research at Weill Cornell Medicine.
In developing their new model, the researchers focused on a protein called VPS35, which plays a crucial role in the transportation of molecules within cells. Mutations in the VPS35 gene have been linked previously to a familial form of Parkinson’s disease. For the development of the new model, the team genetically engineered mice with a targeted deletion of the VPS35 gene specifically in the rod cells of the retina. Mice with VPS35 knocked out showed an accumulation of alpha-synuclein aggregates, which is a known feature of Parkinson’s disease. These aggregates eventually formed large, insoluble inclusions reminiscent of Lewy bodies, a classic pathological marker of the disease.
Sung highlighted the model’s utility for future research: “We think this explains why we saw such a strong effect of knocking out this protein.” The model offers a more natural progression of disease pathology more closely aligned with how it develops in humans. As such, it can be a new, valuable tool to study Parkinson’s disease mechanisms and for testing potential new therapies.
In addition to its research applications, the new model could inform new methods for earlier diagnosis. The study found that even in young, three-month-old mice, researchers could detect disease-associated changes using a standard ophthalmological device called a fundoscope. This revealed bright spots of autofluorescence due to lipofuscin molecules associated with alpha-synuclein aggregates. The Sung lab is now planning a clinical trial to explore this method as a diagnostic tool for detecting Parkinson’s disease in humans.
The study also paves the way for exploring the role of VPS35 in other neurodegenerative diseases. Sung noted, “We expect this to be the beginning of a very interesting exploration,” hinting at future investigations into Alzheimer’s disease, for which VPS35 mutations are also implicated.