Karen McFarland, Ph.D.

karen.mcfarland@neurology.ufl.edu

Research Interests

How do changes in gene expression drive pathogenic phenotypes in neurodegenerative diseases? And how do these differences in gene expression arise?

Alterations in gene expression levels are a hallmark of many neurodegenerative diseases. In some instances, gene expression changes often precede overt expression of disease phenotypes. Several families of RNA binding proteins regulate the stability, splicing and transport of mRNAs along the axons. Several of these RBPs are found mutated in or interact with other proteins involved in neurodegenerative diseases highlighting the important role of proper RNA homeostasis within the brain.

Alzheimer’s disease and related dementias

Gene expression changes are wide-spread throughout the brain in Alzheimer’s disease (AD) patients as well as those patients with Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Of the many changes that are observed in AD brains is an increase in the retention of introns within mature mRNA transcripts. Intron retention (IR) is the least studied of alternative splicing events. Early studies concluded that IR was a consequence of errors in normal splicing events. However, with the advent of deep RNA-sequencing studies, introns are thought to be actively retained in mature mRNAs providing an additional mechanism to regulate the levels of mRNA independent of transcription.

mRNA transcripts containing a retained intron typically have one of three fates. First, the mature mRNA transcript containing the retained intron are transported to the cytoplasm triggering non-sense mediated decay (NMD) resulting in decreased transcript levels. Second, mRNAs containing retained introns accumulate inside the nucleus providing a ready pool of transcripts to be spliced upon an external stimulus. Third, mRNAs with the retained intron—once transported to the cytoplasm and translated into protein—can produce a protein isoform containing a new domain having either dominant-negative effects or a new function within the cell. Studies in our lab aim to understand the function of this and other splicing alterations in mouse models of dementia.

Amyotrophic lateral sclerosis and fronto-temporal dementia (ALS-FTD)

Mutations in ubiquilin-2 (UBQLN2) are found in both familial and sporadic forms of FTD and ALS. UBQLN2 was recently demonstrated to interact with RNA binding proteins. We aim to understand the role of UBQLN2 in normal RNA homeostasis and to determine how ALS-FTD associated mutations in UBQLN2 affect this process. Results from these studies will lead to an understanding of how various UBQLN2 mutations lead to such diverse phenotypes in ALS and FTD. Additionally, this work will inform the interpretation of various UBQLN2 mutations in clinical settings.

Spinocerebellar ataxias (SCAs)

Spinocerebellar ataxia type 10 (SCA10) is caused by a non-coding repeat expansion in ATAXIN 10. The repeat expansion is transcribed and accumulate as RNA foci which bind and sequester RNA binding proteins. Attempts by our lab to understand differences in clinical phenotypes in SCA10 patients has led to the revelation that subsets of SCA10 patients carry repeat expansions that are highly interrupted with various repeat motifs. These interrupted repeat motifs correlate with differences in repeat stability as well as with extracerebellar phenotypes. These data together lead to the hypothesis that clinical phenotypes in SCA10 are driven by differential RNA binding protein sequestration by the repeat expansions, which recognize their target RNA by consensus binding motifs.  Thus, we postulate a likely mechanism is that the underlying differences in repeat expansion composition drive clinical phenotypes and predict differential sequestration of RNA binding proteins, and hence, different downstream effects.

Education

2004 – Ph.D., Biology, Program in Cellular, Developmental and Molecular Biology, University of Rochester, Rochester, NY.
1999 – M.S., Biology, Program in Cellular, Developmental and Molecular Biology, University of Rochester, Rochester, NY.
1997 – B.S.  Biology, Magna Cum Laude, concentration in Molecular Biology, King’s College, Wilkes-Barre, PA.

Professional Experience

Research Assistant Professor, Department of Neurology, University of Florida, Gainesville, FL. – 2010 – present
Postdoctoral Research Fellow, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital, Department of Neurology, Charlestown, MA. Laboratory of Jang-Ho Cha, M.D., Ph.D. – 2007 – 2010
Postdoctoral Research Associate, University of Virginia, Department of Pathology (Neuropathology), Charlottesville, VA. Laboratory of James W. Mandell, M.D., Ph.D. – 2004 – 2006
Graduate Student, University of Rochester, Rochester, NY, Department of Biology. Laboratory of Donald A. Kane, Ph.D. – 1997 – 2004

Teaching Experience

Seminar Preview Leader, Neuroscience Graduate Program, University of Virginia, Charlottesville, VA. – 2005

Co-Instructor, Current Topics in Neuroscience, University of Virginia, Neuroscience Graduate Program, Charlottesville, VA. – 2005

Teaching Assistant, Molecular Genetics Laboratory, University of Rochester, Department of Biology, Rochester, NY. – 1997 – 1998

Student Laboratory Aide, Vertebrate Biology & Cell and Developmental Biology Courses, King’s College, Wilkes-Barre, PA. -1996 – 1997

Honors & Awards

Berman Fellowship in Alzheimer’s Disease, University of Florida, Department of Neurology, Gainesville, FL. – 2017

BeHEARD Assay Depot/Rare Genomics Institute Challenge Winner, Plasmid Acquisition from Addgene – 2013

Best Other Movement Disorder (OMD) Abstract, 23rd Annual Symposium on the Etiology, Pathogenesis, and Treatment of Parkinson’s Disease and Other Movement Disorders, Baltimore, MD. – 2009

Best Basic Science Poster, University of Virginia, Department of Pathology Research Retreat, Charlottesville, VA. – 2004

Holtfreter Graduate Student Fellowship, University of Rochester, Department of Biology, Rochester, NY. – 1997 – 2001

Graduate Student Presentation Award, University of Rochester, Department of Biology, Rochester, NY. – 2000

Graduate Student Teaching Award, University of Rochester, Department of Biology, Rochester, NY. – 1999

NSF Research Experience for Undergraduates (REU) Fellowship, Undergraduate Student, Duquesne University, Department of Biology, Pittsburgh, PA. – 1996

Member, Alpha Epsilon Delta Premedical Honor Society, King’s College, Pennsylvania Lambda Chapter – 1996 – 1997

Professional Society Affiliations

Society for Neuroscience

Publications

Kane DA, McFarland KN, Warga Rm.Mutations in half baked/E-cadherin block cell behaviors that are necessary for teleost epiboly. Development 2005; 132(5): 1105-16.

McFarland KN, Warga RM, Kane DA. Genetic locus half baked is necessary for morphogenesis of the ectoderm. Developmental dynamics: an official publication of the American Association of Anatomists.  2005; 232(2):390-406.

McFarland KN, Wilkes SR, Koss SE, Ravichandran KS, Mandell JW. Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly. The Journal of neurosciene: the offiical journal of the Society for Neuroscience. 2006; 26(30):7885.97.

Benn CL, Sun T, Sadri-Vakili G, McFarland KN, DiRocco DP, Yohrling GJ, Clark TW, Bouzou B, Cha JH. Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008; 28(42):10720-33. NIHMSID: NIHMS74161

Riley BB, Sweet EM, Heck R, Evans A, McFarland KN, Warga RM, Kane DA. Characterization of harpy/Rca1/emi1 mutants: patterning in the absence of cell division.  Developmental dynamics : an official publication of the American Association of Anatomists. 2010; 239(3):828-43.

A complete list of publications can be found here.