A recent study led by Weill Cornell Medicine researchers introduces a groundbreaking preclinical model that provides a unique platform for investigating Parkinson’s disease mechanisms and proposes a potentially straightforward method for early disease detection.
In their study, which was published on July 23 in Nature Communications, the researchers demonstrated that disrupting a crucial element involved in protein transportation within the light-sensing rod cells of mice leads to the accumulation of alpha-synuclein protein aggregates in the retina, a hallmark of Parkinson’s disease in patients.
Dr. Ching-Hwa Sung, the Betty Neuwirth Lee and Chilly Professor in Stem Cell Research at Weill Cornell Medicine, described this model as a one-of-a-kind approach that mirrors human Parkinson’s disease more closely than other existing mouse models.
The primary authors of the study included postdoctoral researchers Drs. Cheng Fu, Nan Yang, Nobuyuki Nakajima, and Satoshi Iraha from the Sung Laboratory, alongside Dr. Jen-Zen Chuang, an associate professor of cell biology research in ophthalmology at Weill Cornell Medicine, and Dr. Neeta Roy, an assistant professor of neuroscience research in ophthalmology at Weill Cornell Medicine.
Parkinson’s disease, the second most prevalent neurodegenerative disorder following Alzheimer’s, affects roughly one million Americans, with about 90,000 new cases diagnosed annually in the United States. While commonly known for its impact on movement, Parkinson’s can also manifest through various other symptoms affecting vision, cognition, sleep patterns, and gastrointestinal function.
In their research, the team genetically modified mice to lack the VPS35 protein gene specifically in rod cells, the primary light-sensing neurons in the retina. VPS35 plays a role in the sorting and transportation of molecules within cells, including the disposal of abnormal proteins. Mutations in the VPS35 gene have been associated with a familial form of Parkinson’s disease.
The researchers observed that the VPS35-deficient rod cells began to lose synaptic connections at a young age, leading to visual impairment akin to that seen in Parkinson’s patients. This loss triggered the formation of alpha-synuclein aggregates, and eventually, as the affected rod cells deteriorated, the mouse retinas showcased insoluble inclusions resembling Lewy bodies, a distinctive Parkinson’s disease pathology marker containing alpha-synuclein aggregates.
An analysis of VPS35’s interactions with other proteins revealed its dual role in clearing aggregated alpha-synuclein and preventing its accumulation, providing insight into the significant impact of disrupting this protein.
Dr. Sung emphasized the potential of this novel model for investigating disease mechanisms and testing potential treatments, highlighting its rapid disease progression and avoidance of artificial modifications to alpha-synuclein compared to existing models.
The study findings also suggest a promising avenue for Parkinson’s disease detection, as the researchers were able to use a standard ophthalmological device to detect autofluorescence signals in three-month-old mice lacking rod-cell VPS35, a method they plan to explore in clinical trials.
Dr. Sung intends to expand the use of VPS35-knockout mice to study Alzheimer’s disease, given the link between VPS35 mutations and that disorder.
As Dr. Sung looks forward to further exploration, the study’s research was supported in part by the National Eye Institute and the National Institute on Aging, both components of the National Institutes of Health, through various grant awards.
