Developmental defects in Huntington's disease show that axonal growth and microtubule reorganization require NUMA1.

Although the classic symptoms of Huntington's disease (HD) manifest in adulthood, neural progenitor cell behavior is already abnormal by 13 weeks' gestation. To determine how these developmental defects evolve, we turned to cell and mouse models. We found that layer II/III neurons that normally connect the hemispheres are limited in their growth in HD by microtubule bundling defects within the axonal growth cone, so that fewer axons cross the corpus callosum.

Increasing brain palmitoylation rescues behavior and neuropathology in Huntington disease mice.

Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective huntingtin-dependent trafficking.

Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin.

Chronic exposure to stress is a major risk factor for neuropsychiatric disease, and elevated plasma corticosterone (CORT) correlates with reduced levels of both brain-derived neurotrophic factor (BDNF) and hippocampal neurogenesis. Precisely how these phenomena are linked, however, remains unclear. Using a cortico-hippocampal network-on-a-chip, we find that the glucocorticoid receptor agonist dexamethasone (DXM) stimulates the cyclin-dependent kinase 5 (CDK5) to phosphorylate huntingtin (HTT) at serines 1181 and 1201 (S1181/1201), which retards BDNF vesicular transport in cortical axons.