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 reagentmediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons., a genetically defined progressive neurodegenerative disorder, is characterized by abnormal involuntary movements, cognitive disability, and psychiatric symptoms (1). The pathogenesis of HD is due to an expanded CAG repeat in the huntingtin (HTT) gene, which encodes the protein Htt. Mutant Htt (mHTT) features an increased number of glutamines (Q > 36) near the N terminus. The striking atrophy and loss of striatal medium-sized spiny neurons (MSNs) in the HD brain are accompanied by atrophy of the cortex (2). The mechanisms by which mHTT induces dysfunction and death of neurons are actively explored (3). It has been shown that mHTT has an impact on axonal trafficking and signaling, synaptic function, gene expression, mitochondrial function, calcium homeostasis, and proteostasis (4, 5). Thus, mHTT plays a central role in HD pathogenesis, an assertion fully supported by recent studies in the BACHD model of HD (6).One productive line of inquiry regarding HD pathogenesis focuses on brain-derived neurotrophic factor (BDNF), which sustains neurons of the corticostriatal circuit (7-10). In the corticostriatal circuit, BDNF is produced in cortical neurons and is transported anterogradely in axons before secretion in striatum. Released BDNF binds to tyrosine receptor kinase B (TrkB) on striatal MSNs, resulting in BDNF-mediated signaling. Because MSNs do not produce BDNF, they are largely dependent on cortical neurons for i...