Research Snapshot: Drs. Adamantios Mamais and Matthew J. LaVoie

By Michelle Koidin Jaffee

One aim of Parkinson’s disease research is to better understand how proteins encoded by the LRRK2 gene — mutations of which are a common genetic cause of familial Parkinson’s — could influence development of features of the disease. Now, in the Feb. 13 issue of Stem Cell Reports, a preclinical gene-editing study led by UF neuroscientists provides novel insight into mechanisms of how two such proteins may accumulate in Parkinson’s, findings that could contribute to developing new therapies to thwart the disease process.

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Deficiency of Rab8a and Rab10 in human cells highlight distinct cellular pathways that can contribute to the pathology of LRRK2 Parkinson’s disease and drive alpha-synuclein and tau protein aggregation.

The study, a collaboration of McKnight Brain Institute and Norman Fixel Institute researchers and colleagues at Harvard Medical School, used gene editing to generate a novel series of human stem-cell lines lacking expression of RAB8a or RAB10 molecules, the two most well-validated proteins that LRRK2 influences.

Led by Matthew J. LaVoie, Ph.D., director of UF’s Center for Translational Research in Neurodegenerative Disease, and Adamantios Mamais, Ph.D., M.Sc., researchers used CRISPR-Cas9 genome editing to inactivate RAB8a or RAB10 expression in stem cells derived from healthy human participants.

Then, in neuron models, the researchers analyzed the consequences for two proteins, alpha-synuclein and tau. The findings suggest that RAB8a and RAB10 deficiency may alter levels of the two proteins, highlighting distinct cellular pathways that could contribute to the pathology of LRRK2 Parkinson’s disease.

“Our work identified novel Parkinson’s disease-related consequences associated with two downstream players in the LRRK2 pathway,” LaVoie said. “These new data provide some mechanistic insight into how alpha-synuclein and tau proteins may aggregate in this disease.”

The study builds upon a previous LaVoie collaboration led by Laura Volpicelli-Daley, Ph.D., of the University of Alabama at Birmingham, which found a potential role for RAB10 in presynaptic terminals of the neuron. Together, these two studies shed light on the normal and pathological roles of RAB10, LaVoie said.

“We hope collectively that our work elucidates the early neuronal defects that arise in this neurodegenerative disease, providing the opportunity to develop novel interventions to slow or halt the disease process,” he said.

Current research shows contributors to Parkinson’s include genetics, head injury, lifestyle influences and exposure to chemicals such as pesticides and herbicides. Scientists have found that about 10-15% of Parkinson’s cases are familial, or linked to a direct genetic cause.

Read the paper in Stem Cell Reports.