Dr. Michael Hayden, Research
Supervisor (Medical Genetics)
Dr. Blair Leavitt (Medical
Genetics)
Dr. Jane Roskams (Zoology)
Dr. Wendy Robinson (Medical
Genetics)
EXAMINING COMMITTEE
Chair: Dr. Harold Kasinsky (Zoology)
Supervisory Committee: Dr. Michael Hayden, Research
Supervisor (Medical Genetics), Dr. Blair Leavitt (Medical Genetics) Dr. Wendy
Robinson (Medical Genetics)
University Examiners: Dr. Lynn Raymond (Psychiatry), Dr.
Dessa Sadovnick (Medical Genetics)
External Examiner: Dr. Harry Orr, Department of Laboratory
Medicine and Pathology. University of Minnesota, Minneapolis, MN, USA.
ABSTRACT
Huntington disease (HD) is an adult onset
neurodegenerative disorder that is characterized by motor dysfunction,
cognitive impairment and neuropsychiatric disturbances. HD patients exhibit progressive and
selective neurodegeneration primarily in the striatum and cortex. There is currently
no treatment that can prevent the development of HD or alter its progression. The major
objectives of this thesis were to determine which symptoms of HD are recapitulated
in YAC transgenic mouse models of the disease, to develop a standardized
protocol for therapeutic trials in these mice and to investigate potential
treatments for HD. Two transgenic mouse models of HD were examined that express
huntingtin (htt) with either 72 (YAC72 mice) or 128 (YAC128 mice) glutamines
from a yeast artificial chromosome transgene. While YAC72 mice exhibit a mild phenotype,
YAC128 mice show quantifiable abnormalities that recapitulate the motor and
cognitive deficits in HD. Importantly, YAC128 mice also exhibit selective and
progressive degeneration in the brain, including neuronal loss. To determine
the feasibility of genetic modulation of the disease phenotype, we investigated
the ability of over-expression of wild type htt to prevent striatal neuropathology
in YAC128 mice based on a putative pro-survival function of wild type htt. We
demonstrate for the first time that wild type htt is neuroprotective in the brain.
In YAC128 mice, over-expression of wild type htt prevented atrophy of striatal neurons
but did not significantly improve striatal volume or striatal neuronal numbers.
To determine the feasibility of pharmacologic therapeutic trials in YAC128 mice
we treated mice with cystamine, a transglutaminase inhibitor with other beneficial
characteristics. While cystamine treatment did not improve motor symptoms, this
treatment ameliorated striatal volume loss, striatal neuronal loss and striatal
neuronal atrophy. This trial validates the use of YAC128 mice in therapeutic trials
for HD as we reproduced all of the differences between YAC128 and WT mice in
this therapeutic trial. Overall, this thesis demonstrates that the YAC128 mouse
model of HD recapitulates the progressive motor dysfunction, cognitive deficits
and selective neurodegeneration of HD. As such, these mice can be used for
studies of HD pathogenesis and in preclinical therapeutic trials for HD.
SELECTED PUBLICATIONS
Van
Raamsdonk JM, Pearson J, Rogers D, Bissada N, Vogl AW, Leavitt BR,
Hayden MR (2005). Loss of wild type huntingtin influences
motor dysfunction and survival in the YAC128 mouse model of Huntington disease.
Hum Mol Gen 10(14): 1379-1392.
Van
Raamsdonk JM, Pearson J, Slow EJ, Hossain SM, Leavitt BR, Hayden MR (2005). Cognitive Dysfunction Precedes Neuropathology and
Motor Abnormalities in the YAC128 Mouse Model of Huntington’s Disease. J. Neurosci 25(16): 4169-80.
Pinto JT, Van
Raamsdonk J, Leavitt, BR, Hayden MR, Krasnikov BF, Cooper AJL (2005). Treatment of YAC128 Mice and Their Wild-Type
Littermates with Cystamine Does not Lead to Its Accumulation in Plasma or Brain:
Implications for the Treatment of Huntington Disease. J. Neurochem.(in press).
Van
Raamsdonk JM, Pearson J, Bailey CDC, Rogers D, Johnson GVW, Hayden MR, Leavitt BR (2005). Cystamine Treatment Ameliorates
Striatal Neuropathology in YAC128 Mouse Model of Huntington’s Disease. J.
Neurochem.(in press).
Van
Raamsdonk JM, Pearson J, Rogers DA, Lu G, Hayden MR, Leavitt BR.
Ethyl- EPA Treatment Improves Motor Dysfunction, but not Neurodegeneration in HD Mice. Experimental Neurology (in press).
Slow, EJ, Van
Raamsdonk JM, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Yang Y-Z, Bissada N, Li X-J, Simpson EM, Gutekunst C-A,
Leavitt BR, Hayden MR (2003). Selective striatal neuronal loss in a YAC128
mouse model of Huntington disease. Hum Mol Genet 12(13): 1555-1567.
Leavitt BR*, Van
Raamsdonk J*, Shehadeh J, Fernandes H, Graham RK,
Wellington CL, Raymond LA, Hayden MR. Wild-Type Huntingtin
Protects Neurons from Excitotoxicity. Submitted to Journal of
Neurochemistry *equal contribution.
Van
Raamsdonk JM, Murphy Z, Pearson J, Slow EJ, Leavitt BR, Hayden MR. Selective Degeneration and Nuclear Localization of Mutant
Huntingtin in the YAC128 Mouse Model of Huntington Disease. Submitted to Human
Molecular Genetics.
AWARDS
2004-2005 Landmark Graduate Award for HD research
2001-2004 CIHR Doctoral Research Award
2001-2004 MSFHR Doctoral Trainee Award
2001-2002 Kearns Award for HD Research
1999-2001 NSERC PGS B Scholarship
1999-2001 UBC Faculty of Medicine Grant Supplement Award
1997-1999 NSERC PGS A Scholarship
1997-1999 McMaster Entrance Scholarship
1996-1997 University of British Columbia Wesbrook Scholar
1993-1997 University of British Columbia Chancellor’s Scholarship
1993-1997 Canada Scholarship in Science and Engineering
1995-1997 Charles and Jane Banks Scholarship for Science
1996-1997 Canada Scholarship Corporate Award
1993-1997 Dean’s Honours List University of British
Columbia
1994-1996 Science Scholar - University of British Columbia
1994-1995 J. Fred Muir Scholarship in Science and
Engineering
1994 Hewlett-Packard Prize - University of British
Columbia
GRADUATE STUDIES
Field of Study: Huntington disease
Courses:
MEDG 520 Advanced Human Molecular Genetics Carolyn Brown
MEDG 530 Advanced Human Genetics Drs. Jan Friedman & Elizabeth
Simpson
MEDG 540 Medical Genetics Seminar Drs. Carolyn Brown &
Fred Dill
