title: Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease.
abstract: Although the huntingtin gene is expressed in brain throughout life, phenotypically Huntington's disease (HD) begins only in midlife and affects specific brain regions. Here, to investigate regional vulnerability in the disease, we used functional magnetic resonance imaging (fMRI) to translationally link studies in patients with a mouse model of disease. Using fMRI, we mapped cerebral blood volume (CBV) in three groups: HD patients, symptom-free carriers of the huntingtin genetic mutation, and age-matched controls. In contrast to a region in the anterior caudate, in which dysfunction was linked to genotype independent of phenotype, a region in the posterior body of the caudate was differentially associated with disease phenotype. Guided by these observations, we harvested regions from the anterior and posterior body of the caudate in postmortem control and HD human brain tissue. Gene-expression profiling identified two molecules whose expression levels were most strongly correlated with regional vulnerability - protein phosphatase 1 regulatory subunit 7 (PPP1R7) and Wnt inhibitory factor-1 (WIF-1). To verify and potentially extend these findings, we turned to the YAC128 (C57BL/6J) HD transgenic mice. By fMRI we longitudinally mapped CBV in transgenic and wildtype (WT) mice, and over time, abnormally low fMRI signal emerged selectively in the dorsal striatum. A relatively unaffected brain region, primary somatosensory cortex (S1), was used as a control. Both dorsal striatum and S1 were harvested from transgenic and WT mice and molecular analysis confirmed that PPP1R7 deficiency was strongly correlated with the phenotype. Together, converging findings in human HD patients and this HD mouse model suggest a functional pattern of caudate vulnerability and that variation in expression levels of herein identified molecules correlate with this pattern of vulnerability.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Lewandowski
authors.forename: Yvette
authors.initials: Y
authors.lastname: Bordelon
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brickman
authors.forename: Sergio
authors.initials: S
authors.lastname: Angulo
authors.forename: Usman
authors.initials: U
authors.lastname: Khan
authors.forename: Jordan
authors.initials: J
authors.lastname: Muraskin
authors.forename: Erica Y
authors.initials: EY
authors.lastname: Griffith
authors.forename: Paula
authors.initials: P
authors.lastname: Wasserman
authors.forename: Liliana
authors.initials: L
authors.lastname: Menalled
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.forename: Scott A
authors.initials: SA
authors.lastname: Small
authors.forename: Herman
authors.initials: H
authors.lastname: Moreno
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C509751:PPP1R7 protein, human; D012097:Repressor Proteins; C485569:WIF1 protein, human; D054645:Protein Phosphatase 1