TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington's disease.
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.
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093;
Xiaobei
X
Zhao
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093;
Xu-Qiao
XQ
Chen
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093;
Eugene
E
Han
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093;
Yue
Y
Hu
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093;
Paul
P
Paik
The University of Texas M. D. Anderson Cancer Center, Houston, TX 77054;
Zhiyong
Z
Ding
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697;
Julia
J
Overman
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697;
Alice L
AL
Lau
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030;
Sarah H
SH
Shahmoradian
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030;
Wah
W
Chiu
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
Leslie M
LM
Thompson
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093; chw049@ucsd.edu wmobley@ucsd.edu.
Chengbiao
C
Wu
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093; chw049@ucsd.edu wmobley@ucsd.edu.
William C
WC
Mobley
D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D056404:Chaperonin Containing TCP-1 / Q000235:genetics* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D056656:Lab-On-A-Chip Devices; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D000071058:Huntingtin Protein; D020813:Receptor, trkB; D056404:Chaperonin Containing TCP-1
BACHD mouse model; BDNF transport; Huntington’s disease; TRiC chaperonin; striatal atrophy