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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.

SUBMITTER: Lewandowski NM

PROVIDER: S-EPMC4435974 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease.

Lewandowski Nicole M NM Bordelon Yvette Y Brickman Adam M AM Angulo Sergio S Khan Usman U Muraskin Jordan J Griffith Erica Y EY Wasserman Paula P Menalled Liliana L Vonsattel Jean Paul JP Marder Karen K Small Scott A SA Moreno Herman H

Neurobiology of disease 20121204

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 ag ...[more]

PMID: 23220414

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Dataset Information

Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease.

Publications

Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease.

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