Fig. 4. Proposed model for a disease progress-dependent alteration of activity-dependent BDNF secretion from cortical axons to the striatum. A schematic illustration of cortical presynaptic BDNF secretion in the normal brain or HD brains at the presymptomatic or symptomatic stage. In addition to impaired synthesis and transport of BDNF, I propose that BDNF secretion is also downregulated by mutant huntingtin (htt), probably through altered actions of molecular mechanisms regulating activity-dependent docking or exocytosis of BDNF-containing vesicles. Since mhtt-mediated disruption of BDNF secretion is prominent during the presymptomatic stage of HD, and this could be reversed by selective reduction of mhtt, a combined treatment targeting both the presymptomatic stage of HD and restoration of BDNF expression could be a promising strategy for reversing striatal degeneration in the HD brain.
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