By Michelle Jaffee
New research by McKnight Brain Institute neuroscientists has revealed an interaction between proteins encoded by two genes, LRRK2 and VPS35. This preclinical discovery in a mouse model could accelerate the development of new medications to slow or halt progression of Parkinson’s disease.
Published online Dec. 18 in the journal npj Parkinson’s Disease, the study provides new insights into the biology of LRRK2 as well as drugs developed to inhibit its kinase activity. LRRK2 kinase activity regulates specific aspects of synaptic activity in the brain as well as immunity in the body.
The finding is the latest advance by Matthew J. Farrer, Ph.D., who has made key discoveries involving genetic mutations that can cause Parkinson’s disease. In 2005, Farrer and collaborators first described LRRK2 G2019S in several families in Europe and North America and suggested that it may cause disease by increasing the gene’s kinase activity.
In 2011, Farrer and collaborators published a study implicating another gene, VPS35 D620N, as a cause of Parkinson’s disease. VPS35 encodes the “cargo-recognition complex” of the retromer protein complex, which recycles many protein cargos allowing them to be reused. In dopamine neurons, the cells that die in Parkinson’s disease, one important cargo is the dopamine transporter.
“The retromer is like a cable car that moves cargo (proteins) to enable their reuse,” said Farrer, a UF professor of neurology. “When dopamine neurons fail to recycle cargo, it’s a problem.”
Now, Anthea Mengfei Bu, Ph.D., the first author, has demonstrated how LRRK2 exercises “kinase-dependent” control over dopamine transporter recycling in dopaminergic neurons in VPS35 mouse models. To test this in real time, the researchers used amphetamine, a potent stimulator of dopamine release acting via the dopamine transporter. They showed that a drug that specifically inhibits LRRK2’s kinase activity makes the VPS35 D620N model behave like a normal mouse.
“Parkinson’s disease is the most common neurodegenerative movement disorder, and that can be directly and unequivocally attributed to the loss of dopamine neurons,” Farrer said. “This study is a major win for neuroprotection in Parkinson’s disease.”
While further preclinical studies are needed to understand other roles of LRRK2 activity in dopamine circuits, the results of this study could accelerate drug development and testing in future human clinical trials, Farrer said.
Scientists today have linked about 10-15% of Parkinson’s cases to a direct genetic cause. Current research shows other contributors include head injury, lifestyle influences and exposure to chemicals such as pesticides and herbicides.
Bu is a former Farrer lab trainee and was successfully awarded her Ph.D. on the basis of her doctoral studies at the MBI.