Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease
| Autor: | Paula Wasserman, Liliana B. Menalled, Nicole M. Lewandowski, Jean Paul G. Vonsattel, Jordan Muraskin, Herman Moreno, Usman A. Khan, Scott A. Small, Erica Y. Griffith, Sergio Angulo, Karen Marder, Adam M. Brickman, Yvette Bordelon |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Genetically modified mouse Pathology medicine.medical_specialty Huntingtin Mice Transgenic Nerve Tissue Proteins Striatum CBV Biology YAC128 Article lcsh:RC321-571 Mice Huntington's disease Protein Phosphatase 1 Huntingtin Protein medicine Animals Humans lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Adaptor Proteins Signal Transducing Aged Neurons medicine.diagnostic_test Nuclear Proteins PPP1R7 Human brain Middle Aged medicine.disease Magnetic Resonance Imaging Phenotype Corpus Striatum Repressor Proteins Disease Models Animal Huntington Disease medicine.anatomical_structure Gene Expression Regulation Neurology Cerebrovascular Circulation WIF-1 Mutation Female Functional magnetic resonance imaging Neuroscience |
| Zdroj: | Neurobiology of Disease, Vol 52, Iss, Pp 84-93 (2013) |
| Popis: | Although the huntingtin gene is expressed in brain throughout life, phenotypically Huntington's disease (HD) begins only in midlife to affect 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 (WIF1). 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 an anatomo/functional pattern of caudate vulnerability and that variation in expression levels of herein identified molecules correlate with this pattern of vulnerability. |
| Databáze: | OpenAIRE |
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