TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington's disease

Xiaobei Zhao, Xu Qiao Chen, Eugene Han, Yue Hu, Paul Paik, Zhiyong Ding, Julia Overman, Alice L. Lau, Sarah H. Shahmoradian, Wah Chiu, Leslie M. Thompson, Chengbiao Wu, William C. Mobley

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.

Original languageEnglish (US)
Pages (from-to)E5655-E5664
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number38
DOIs
StatePublished - Sep 20 2016
Externally publishedYes

Keywords

  • BACHD mouse model
  • BDNF transport
  • Huntington's disease
  • Striatal atrophy
  • TRiC chaperonin

ASJC Scopus subject areas

  • General

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