Dr. Nikolaus McFarland
Targeting Parkinson Disease and Related Disorders
Assistant Professor, Neurology;
Faculty, UF Movement Disorder Center;
Investigator, Movement Disorders Research Group and CTRND
Clinical Research Fellow, Movement Disorders, Dept Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 2006-10
Neurology Residency/Internship, University of Virginia Health System, 2002-06
MD, University of Rochester School of Medicine & Dentistry, 2002
PhD, University of Rochester School of Medicine & Dentistry, 2001
BA, University of Chicago, 1992
Contact Dr. McFarland
Office Phone: 352-273-5550
Research Focus and Aims:
My research focuses on understanding the pathological mechanisms of Parkinson disease and related disorders (atypical parkinsonisms) and in particular the role of alpha-synuclein in cell toxicity and neurodegeneration. A major hallmark of neurodegenerative disorders, including Parkinson disease, is abnormal protein aggregation and deposition. In Parkinson disease and related disorders, intracellular inclusions called Lewy bodies are found. A principal component of these Lewy bodies is alpha-synuclein. Abnormal folding, aggregation, and deposition of alpha-synuclein are believed to be central to the development of neuronal dysfunction and degeneration. A primary goal of my research is thus to elucidate the mechanisms of alpha-synuclein toxicity and to characterize molecular mediators that may enhance or rescue its toxicity. Work involves use of cellular, neuronal, and animal models that employ alpha-synuclein overexpression and allow for testing of various genes, molecules, and compounds that may modify toxicity and have the potential for novel therapeutics.
Current research aims and techniques include:
- Rab protein and alpha-synuclein interactions: Recent data from yeast suggest that alpha-synuclein results in toxicity, likely due to interference in intracellular trafficking and vesicle accumulation. The discovery that these deficits can be ameliorated by expression of specific Rab proteins—members of the Ras superfamily of GTP-bindings proteins—suggests that alpha-synuclein accumulation may interfere with normal Rab function. These proteins may also play an important role in preventing formation toxic synuclein aggregates. We are studying the mechanisms whereby Rab protein expression confers protection against alpha-synuclein induced toxicity in both cellular and animal models of Parkinsonism. Additional studies examine Rab protein interactions with alpha-synuclein in pathological brain specimens from Parkinson disease patients and other related disorders.
- Sirtuins and neurodegenerative disease: Sirtuins are highly conserved proteins and members of the histone deacetylase (HDAC) family, thought to be involved in aging and neurodegenerative disease. Recently novel compounds were discovered that specifically inhibit sirtuin 2 (SIRT2) and rescue alpha-synuclein toxicity in several Parkinson disease model systems. The mechanism of this neuroprotection is unclear, but these compounds raise the possibility of a novel therapeutic approach to Parkinsons. We are investigating the effects SIRT2 inhibition in both cells and our rat model of Parkinsonism using targeted viral (AAV) overexpression of the alpha-synuclein gene. In contrast to toxin-based models, this model results in progressive dopamine cell toxicity over weeks and allows testing of various genes or compounds, such as the SIRT2 inhibitors, which may prevent or ameliorate toxicity
- Urate and Parkinson disease: Elevated serum urate levels correlate with lower incidence and slower progression rate in Parkinson disease, but the mechanism of protection is unclear. We have an active collaboration with Dr. Michael Schwarzschild at Massachusetts General Hospital (MGH) to study urate and its metabolic precursors in pathological brain tissue from Parkinson disease patients and related disorders.
- Initiative for Atypical Parkinsonism: In the Movement Disorders Clinic over the next few years we are developing a multidisciplinary group and approach to help those with Parkinson-plus syndromes, or atypical Parkinsonism such as Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA). In contrast to classical Parkinson disease, these disorders often do not respond as well to dopamine therapies, progressive more rapidly, and have additional features such as frequent falls, bulbar symptoms, and cognitive decline. These disorders are also particularly challenging to caregivers. More research is clearly needed for better diagnostics and therapeutics.
Join the team!
We welcome applications from undergraduate/graduate students and post-doctoral fellows who would like to join the lab team
- McFarland NR, Lee J-S, Hyman BT, McLean PJ. Comparison of transduction efficiency of recombinant AAV serotypes 1, 2, 5, and 8 in the rat nigrostriatal system. J Neurochem 2009:109(3):838-45.
- McFarland NR, Fan Z, Xu K, et al. Alpha-synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of Parkinson disease. J Neuropathol Exper Neurology 2009: 68(5):515-524.