Dr. Matt Farrer is critically acclaimed for his work in the genetics and neuroscience of Parkinson’s disease. His inspiration to apply genetic analysis to complex neurologic disorders came from early work as a care assistant of patients and families with neurologic and psychiatric disorders. Dr. Farrer earned first degree in Biochemistry with a Doctoral degree in Molecular and Statistical Genetics from St. Mary’s Hospital Medical School, UK. He completed a Fellowship in Medical Genetics at the Kennedy-Galton Centre, UK, and in Neurogenetics at Mayo Clinic. Dr. Farrer became an Assistant Professor of Molecular Neuroscience in 2000, where he opened his first laboratory to predict and prevent Parkinson’s disease. Dr. Farrer became a tenured Professor in 2006, a Mayo Consultant and subsequently a Distinguished Mayo Investigator. In 2010, Dr. Farrer was awarded a Canada Excellence Research Chair to build the Centre for Applied Neurogenetics and Neuroscience at the University of British Columbia, Vancouver, Canada. He came a Professor of Medical Genetics. The Province of British Columbia subsequently awarded him the Don Rix Chair in Precision Medicine and his team had many notable accomplishments, including several new genes and mouse models for Parkinson’s disease. The team also implemented high-throughput sequencing in pediatric seizure disorders and neonatology in clinical service. The former was funded through the Medical Services Plan of British Columbia, and was a first for Canada.
In 2019, Dr. Farrer accepted an endowed chair at the Norman Fixel Institute for Neurological Diseases (thanks to a generous endowment from the Lauren and Lee Fixel Family Foundation). Dr. Matt Farrer also directs the UF Clinical Genomics Program. As such he currently has appointments and affiliations in the UF College of Medicine’s Neurology and Pathology Departments, Clinical and Translational Science Institute, the Evelyn F. and William L. McKnight Brain Institute, the Center for Translational Research in Neurodegenerative Disease, the Center for Neurogenetic in addition to the Norman Fixel Institute for Neurological Diseases.
Dr. Matt Farrer’s research team have made several influential discoveries in neurogenetics, and have been at the forefront of every major genetic discovery in Parkinson’s disease. His team have published over 350 publications in the field. In this journey, Dr. Farrer has had the rare privilege to work with neurologists, patients and families from many parts of the globe: from Guam in the South Pacific, where Chamorro families may develop Parkinson-Dementia Complex, to the Faroe Islands in the North Atlantic where Parkinson’s disease has a higher incidence. His team are currently involved in projects in Japan and Korea on multiple system atrophy, a rare form or parkinsonism with prominent autonomic dysfunction, to studies with familial and young-onset parkinsonism in ethnic Taiwanese. Dr. Farrer has also worked with the National Institute of Neurology and Berber populations in Tunisia, North Africa since 2005, and more recently has been working with Mennonite families from the Canadian prairies.
Dr. Farrer’s work in pedigree-based genetics originally led to the discovery of multiplications in the alpha-synuclein gene (SNCA), that demonstrated a direct ‘dosage’ relationship between alpha-synuclein copy number, expression and the age of onset and severity of Lewy body parkinsonism. In addition, his research team helped identify leucine-rich repeat kinase 2 (LRRK2), and specifically the p.G2019S and p.G2385R mutations. His team showed these variants to be the commonest known genetic cause of Parkinson’s disease, globally. Curiously, in both instances, these Lrrk2 heterozygotes are mostly descended from a common ancestral founder, and there is strong genetic evidence for positive selection. Genetic variability in the Lrrk2 locus has also been implicated in a number of immune/inflammatory disorders. Dr. Farrer’s team also linked mutations in dynactin p150 (DCTN1 CAP-Gly domain mutations), vacuolar protein sorting 35 (VPS35 p.D620N), receptor-mediated endocytosis-8 (DNAJC13 p.N855S) and heat shock protein 40 (DNAJC12 null mutations) to different subtypes of parkinsonism. His team continue to generate and analyze high-throughput sequencing data, and customize bioinformatics tools to ensure those insights are accessible for clinical interpretation and scientific modelling.
Dr. Farrer’s neuroscience is focused on the creation and characterization model systems. Its foundation is mutant genes his team has identified that lead to Parkinson’s disease. Mouse modelling is pursued in C57Bl/6J mice using a combination cre recombinase expression and loxP genetic engineering. Now, combined with adeno-associated virus promoted cre recombinase expression, we have the tools to turn on/off mutant genes temporally, and in any cell type. Prior studies include modeling alpha-synuclein overexpression, and in the dopaminergic system, and include the development of RNA interference strategies for gene silencing in partnership with Alnylam and Ionis Therapeutics. A caveat is that native monomeric alpha-synuclein expression is an important determinant of neurotransmission and vesicular trafficking. In Lrrk2 p.G2019S mutation suggested that competitive kinase inhibition may be a viable therapeutic option to halt disease progression in many patients, and perhaps may prevent disease altogether. The Lrrk2 protein regulates endosomal cargo sorting for autophagy, in part through Rab protein phosphorylation, actin and tubulin-mediated vesicular trafficking.
While Dr. Farrer’s team have characterized cDNA, BAC overexpressor and iatrogenic ‘seeding’ models, the majority of the laboratory effort has focused on ‘floxed’ gene knock-out and mutant knock-in models. Arguably, these models of gene dysfunction are most physiologically faithful of the human condition. Methods include studies of behavior, neurotransmitter release in vivo and ex vivo in brain slices, in combination with immunohistochemistry, biochemistry and pharmacology. Rodent and human studies have also focused on positron emission tomography of the nigral-striatal system. Much of the current work seeks to understand the precise molecular machinery for Parkinson’s disease, and is largely based on Dr. Farrer’s discoveries in human genetics.