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

TLDR

Huntington’s disease pathogenesis involves many proposed pathways, yet their in vivo effects have rarely been compared to human patient data. The study aims to assess how well mechanistically driven and genetic HD models reproduce the striatal gene‑expression profile seen in human HD. Using the R6/2 transgenic mouse and various toxin‑ and BDNF‑deficient rodent models, the authors profiled striatal gene expression to evaluate model fidelity. BDNF‑deficient models best matched human HD, implicating loss of trophic support and cortical dysfunction as key drivers of striatal degeneration, while mitochondrial toxin‑induced lesions follow distinct pathways, leading to a testable, region‑specific pathogenesis model.

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 α 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.