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 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.

Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

“…These could be classified into six Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, confirming the observed alterations in metabolic pathways ( 38 ) and further identifying changes in axon sprouting and neurodegenerative pathways ( Dataset S2 ). These studies revealed an additional down-regulated regulatory subunit of protein phosphatase 1 (PPP1R7) ( 39 , 40 ). Taken together, these data reveal imbalances in dopaminergic and glutamatergic pathways in the early postnatal period of tgHD rats sufficient to explain the behavioral phenotype.…”

The power of using functional fMRI on small rodents to study brain pharmacology and disease

“…A lot of preclinical neuroscience work is performed on transgenic rodent models for neurodegenerative diseases such as: AD, PD, and HD, which are characterized by deposition of misfolded proteins (proteinopathies) in the brain. In AD and HD, the presence of amyloid plaques and huntingtin, respectively, are hypothesized to affect cortical functioning as shown by diminished fMRI responses to sensory stimuli ( Lewandowski et al, 2013 ; Sanganahalli et al, 2013 ; see Figure 8 for an example). Moreover, entire neuronal networks seem affected ( Liu et al, 2014 ), as shown by altered functional connectivity during rsfMRI ( Shah et al, 2013 ; Ferris et al, 2014 ; Figure 9 ) even in early disease stages before the proteinopathy establishes ( Grandjean et al, 2014b ).…”

Longitudinal transcriptomic dysregulation in the peripheral blood of transgenic Huntington’s disease monkeys

“…Interestingly, LXN was previously shown to be an important regulator of hematopoiesis [31-33], while deficiencies in peripheral blood functions of HD patients have been widely reported, including immune responses [34-36]. Furthermore, the Wnt signaling cascade, which FZD8 is a component of, is increasingly being reported as an important regulator of the cellular responses to mHTT in HD [37-39]. Transcriptome changes in human HD patients can be significantly influenced by other co-existing pathology unrelated to HD, which arguably would be a less pervasive influence in HD monkeys.…”