Huntingtin associated protein and neuropathology

Xiao-Jiang LI

Department of Human Genetics, Emory University, Atlanta, GA USA

Huntingtin associated protein-1 (Hap1) is a neuronal protein that associates with huntingtin, a polyglutamine-containing protein for Huntington’s disease that is characterized by movement disorder, memory loss, and depression. Although Hap1 and huntingtin are known to be involved in intracellular trafficking, whether and how the impairment of Hap1-associated trafficking leads to neurological pathology and symptoms remains to be seen. We generated conditional Hap1 knockout mice in which Hap1 expression can be selectively eliminated in specific types of neurons.We find that Hap1 is abundantly expressed in orexin (hypocretin)-producing neurons (orexin neurons), which are distinctly distributed in the hypothalamus and play an important role in the regulation of feeding and behavior. Conditional Hap1 knockout mice with selective deplete depletion of Hap1 in orexin neurons show process fragmentation of these neurons and reductions in food intake, body weight, and locomotor activity. Hap1 is stabilized by its interacting protein, Ahi1. Depletion of Ahi1 in the brain neurons via the Cre-Loxp system leads to the reduced level of Hap1 and the depressive phenotypes of mice. Furthermore, neuronal deficiency of Ahi1 and Hap1 causes impaired endocytic trafficking of TrkB, a receptor for BDNF that is important for depression and emotion. These results suggest that Hap1 is involved in endocytic sorting and trafficking of TrkB receptor and that impaired TrkB endocytosis may contribute to the neuropathology of Huntington disease and other neurological disorders.