Huntingtin-associated protein-1 interacts with pro-brain-derived neurotrophic factor and mediates its transport and release.
Brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain development and synaptic plasticity. It is synthesized as a precursor (pro-BDNF), sorted into the secretory pathway, transported along dendrites and axons, and released in an activity-dependent manner. Mutant Huntingtin with expanded polyglutamine (polyQ) and the V66M polymorphism of BDNF reduce the dendritic distribution and axonal transport of BDNF. However, the mechanism underlying this defective transport remains unclear. Here, we report that Huntingtin-associated protein-1 (HAP1) interacts with the prodomain of BDNF and that the interaction was reduced in the presence of polyQ-expanded Huntingtin and BDNF V66M. Consistently, there was reduced coimmunoprecipitation of pro-BDNF with HAP1 in the brain homogenate of Huntington disease. Pro-BDNF distribution in the neuronal processes and its accumulation in the proximal and distal segments of crushed sciatic nerve and the activity-dependent release of pro-BDNF were abolished in HAP1(-/-) mice. These results suggest that HAP1 may participate in axonal transport and activity-dependent release of pro-BDNF by interacting with the BDNF prodomain. Accordingly, the decreased interaction between HAP1 and pro-BDNF in Huntington disease may reduce the release and transport of BDNF.
Wu
Linda Lin-yan
LL
Department of Human Physiology and Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia.
Fan
Yongjun
Y
Li
Shihua
S
Li
Xiao-Jiang
XJ
Zhou
Xin-Fu
XF
D000818:Animals; D001369:Axons / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; C096896:HAP1 protein, human; C086055:HTT protein, human; C490758:Hap1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011498:Protein Precursors; C426674:brain-derived neurotrophic factor precursor; C097188:polyglutamine