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McMurray Lab

Research Interest

Overview

Our research is focused on determining the causes and effects of DNA instability in human disease. By examining the diseases which demonstrate neurodegenerative/neuropsychiatric phenotypes such as Huntington's Disease, Spinocerebellar Ataxias, schizophrenia and ataxia Telanglectasia, we hope to elucidate the signaling mechanisms that lead to neuronal death. By studying these mechanisms in model systems, we hope to develop novel pharmacological and molecular approaches to treating human disease.

Planaria

The complex process of regeneration that occurs after bulk tissue loss in planaria, a small non-parasitic flatworm, has been under study for decades to help clarify adult mammalian neurogenesis. We aim to understand the metabolic patterning that occurs both during the organized regrowth of the planarian CNS after gross tissue removal and during normal tissue turnover. Signature metabolites within a tissue can characterize cell response to external stimuli. Global changes in metabolite patterns may be involved in downstream neuroregeneration. Using knockdown of pathways common to both planarian and mammalian neurogenesis, such as wnt/beta-catenin signaling, we probe the metabolic patterning that occurs on a global scale after injury and correlate this information with the time-course of planarian neural structure regrowth. Nanostruture initiated-mass spectrometry (NIMS), a novel method that allows for mapping of metabolites on a single flatworm, enables the monitoring of location- and time-specific changes to the planaria metabolite profile. This spatial profiling is the next step towards determining global metabolic changes after injury that leads to neural progenitor differentiation and integration.

Huntington's Disease

Huntington's disease is part of a group of disorders that arise from a specific genetic mutation called guanine expansion. Expansion is the insertion of extra, repetitive nucleic acid building blocks - represented by the familiar letters - in the DNA of specific genes. Huntington's disease arises from a mutated version of the huntingtin gene that carries an extra DNA segment that repeats the nucleotides cytosine (C), adenine (A), and guanine (G) many times over. DNA expansion is normal to a certain extent; healthy people may have anywhere from 6 and 20 repeats in a gene, but a person with Huntington's has 40 to 80 repeats or more.

Everyone who carries the mutated huntingtin gene will eventually develop the disease. If one of your parents carries the mutation, you have a 50 percent chance of carrying it as well. What's more Huntington's disease generally occurs later in life but the number of CAG repeats vary among affected people. The greater the number of repeats, researchers have found the earlier in life symptoms appear.

Using model mouse systems harboring the mutated huntingtin gene, experiments are currently underway in primary neuronal cells to examine the properties of vesicle trafficking and mitochondrial respiration when compared to controls. Trafficking is being investigated by examining the dynamics of fluorescently conjugated Rab family of proteins involved in synaptic vesicle formation and regulation. In addition, the cell's energy production will be evaluated by assessing mitochondrial health and their distribution in primary neurons. In combination with high-resolution live-cell imaging approaches, we hope to unravel the mechanisms that contribute to neuronal death during the onset of Huntington's.

 

Selected Publications

Mechanisms of trinucleotide repeat instability during human development.
McMurray CT.Nat Rev Genet. 2010 Nov;11(11):786-99. Review.

Coordination between polymerase beta and FEN1 can modulate CAG repeat expansion.
Liu Y, Prasad R, Beard WA, Hou EW, Horton JK, McMurray CT, Wilson SH.J Biol Chem. 2009 Oct 9;284(41):28352-66. Epub 2009 Aug 11.

Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons.
Trushina E, Rana S, McMurray CT, Hua DH. BMC Neurosci. 2009 Jul 8;10:73.

The nucleotide binding dynamics of human MSH2-MSH3 are lesion dependent.
Owen BA, H Lang W, McMurray CT.Nat Struct Mol Biol. 2009 May;16(5):550-7. Epub 2009 Apr 19. Erratum in: Nat Struct Mol Biol. 2009 Aug;16(8):

Single-stranded DNA-binding protein in vitro eliminates the orientation-dependent impediment to polymerase passage on CAG/CTG repeats.
Delagoutte E, Goellner GM, Guo J, Baldacci G, McMurray CT. J Biol Chem. 2008 May 9;283(19):13341-56. Epub 2008 Feb 8.

OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.
Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT. Nature. 2007 May 24;447(7143):447-52. Epub 2007 Apr 22.

Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases.
Trushina E, McMurray CT. Neuroscience. 2007 Apr 14;145(4):1233-48. Epub 2007 Feb 14. Review.

Mutant huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo.
Trushina E, Singh RD, Dyer RB, Cao S, Shah VH, Parton RG, Pagano RE, McMurray CT. Hum Mol Genet. 2006 Dec 15;15(24):3578-91.

(CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition.
Owen BA, Yang Z, Lai M, Gajec M, Badger JD 2nd, Hayes JJ, Edelmann W, Kucherlapati R, Wilson TM, McMurray CT. Nat Struct Mol Biol. 2005 Aug;12(8):663-70. Epub 2005 Jul 17.

McMurray

Cynthia T. McMurray

Senior Staff Scientist/
Life Sciences Division

Department:
Genome Dynamics

Berkeley Lab
One Cyclotron Road
Mailstop: 83R0101
Berkeley, CA 94720
Office: (510) 486-6526
Admin: (510) 486-6285
Fax: (510) 486-6880
Email: ctmcmurray@lbl.gov
Lab Website

Lab Members

Principal Scientist
McMurray, Cynthia

Administrator
Gardner, Mechaka

Lab Manager
Holt, Amy

Scientist; Computer guru
Frankel, Ken

Research Scientists
Budworth, Helen
Canaria, Christie

Postdocs
Chan, Lap Shun (Nelson)
Lee, Do Yup
Xun, Zhiyin (Ella)

Research Assistant
Alford, Brian