Expression Profiling of Huntington's Disease Models Suggests That Brain-Derived Neurotrophic Factor Depletion Plays a Major Role in Striatal Degeneration

Abstract

Many pathways have been proposed as contributing to Huntington's disease (HD) pathogenesis, but generally the in vivo effects of their perturbation have not been compared with reference data from human patients. Here we examine how accurately mechanistically motivated and genetic HD models recapitulate the striatal gene expression phenotype of human HD. The representative genetic model was the R6/2 transgenic mouse, which expresses a fragment of the huntingtin protein containing a long CAG repeat. Pathogenic mechanisms examined include mitochondrial dysfunction; profiled in 3-nitropropionic acid-treated rats, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, and PGC-1␣ knock-out mice; and depletion of brain-derived neurotrophic factor (BDNF) using heterozygous and forebrain-specific BDNF-knock-out mice (BDNF HET , Emx-BDNF KO ). Based on striatal gene expression, we find the BDNF models, both heterozygous and homozygous knock-outs, to be more like human HD than the other HD models. This implicates reduced trophic support as a major pathway contributing to striatal degeneration in HD. Because the majority of striatal BDNF is synthesized by cortical neurons, the data also imply that cortical dysfunction contributes to HD's hallmark effects on the basal ganglia. Finally, the results suggest that striatal lesions caused by mitochondrial toxins may arise via pathways different from those that drive neurodegeneration in HD. Based on these findings, we present a testable model of HD pathogenesis that, unlike most models, begins to account for regional specificity in human HD and the absence of such specificity in genetic mouse models of HD.

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

“…It is believed that transplantation of ADMSCs affected both central and peripheral cholinergic and motor neurons, because an increase in ACh release is related to behavioral activation (Mizuno et al, 1991), and muscarinic agonists improve locomotor behavior in aged animals (Glenn et al, 2004). Moreover, restoration of activity was contributed not only by BDNF involved in dopaminergic function and motor coordination (Strand et al, 2007;Boger et al, 2011) but also by NGF upregulating cholinergic activity (Pongrac and Rylett, 1998;Oosawa et al, 1999;Auld et al, 2001), because neurotrophins, including BDNF and NGF, play roles in skeletal muscle adaptation (Sakuma and Yamaguchi, 2011). The degree of recovery of physical activity was similar among the groups, regardless of injection route and dosage of ADMSCs, suggesting a major role for peripheral effects on neuromuscular transmission.…”

“…Notably, BDNF is also involved in the development of motor coordination (Strand et al, 2007). Several studies have demonstrated that age-and AD-related dysfunctions of the cholinergic system related to physical activity as well as cognitive function are ameliorated by NGF and BDNF treatment (Williams et al, 1986;Casamenti et al, 1994;Kordower et al, 1994;Murray et al, 1994).…”

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

“…Thus, BDNF impairment appears to be a key factor in the pathology of the HD. Indeed, comparative analysis of gene expression profiles of striatal tissues from BDNF knockout mice with those from a postmortem HD patient, and those from HD rodent models including 3-nitropropionic acid-lesioned or transgenic models showed that the BDNF knockout model profile is more comparable to human HD than the other murine HD profiles [114].…”

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

“…To develop a quantitative, cell-based preclinical assay system for HD, we have focused on a well-characterized early feature of disease pathology in both these animal models and HD patients, transcriptional dysregulation in the medium spiny neurons (MSNs) of the basal ganglion, a phenotype with substantial consistency among mouse models and between the models and patients (3)(4)(5)(6). One such dysregulated gene, dopamine receptor D2 (DRD2 or D2), shows high expression levels in MSNs of the indirect pathway (striatopalladial) of the basal ganglion, which are among the earliest to die in HD (reviewed in ref.…”