title: Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites.
abstract: Huntingtin (HTT), the protein mutated in Huntington's disease (HD), controls transport of the neurotrophin, brain-derived neurotrophic factor (BDNF), within corticostriatal neurons. Transport and delivery of BDNF to the striatum are reduced in disease, which contributes to striatal neuron degeneration. BDNF released by cortical neurons activates TrkB receptors at striatal dendrites to promote striatum survival. However, it remains to be determined whether transport of TrkB, the BDNF receptor, depends on HTT and whether such transport is altered in mutant situation. Here we show that TrkB binds to and colocalizes with HTT and dynein. Silencing HTT reduces vesicular transport of TrkB in striatal neurons. In HD, the polyQ expansion in HTT alters the binding of TrkB-containing vesicles to microtubules and reduces transport. Using a combination of microfluidic devices that isolate dendrites from cell bodies and BDNF coupled to quantum dots, we selectively analyzed TrkB retrograde transport in response to BDNF stimulation at dendrite terminals. We show that the retrograde transport of TrkB vesicles within striatal dendrites and the BDNF/TrkB-induced signaling through ERK phosphorylation and c-fos induction are decreased in neurons from an HD mouse model. Together, our findings demonstrate that HTT is a crucial regulator of TrkB trafficking. Transport defects in HD are not restricted to BDNF transport in cortical neurons but also affect trafficking of its ligand-bound receptor in the striatal neurons. This transport alteration may further impair BDNF-TrkB survival signaling within the corticostriatal connection that is most affected in HD.
authors.affiliation: Institut Curie, 75005 Paris, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Liot
authors.forename: Diana
authors.initials: D
authors.lastname: Zala
authors.forename: Patrick
authors.initials: P
authors.lastname: Pla
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mottet
authors.forename: Matthieu
authors.initials: M
authors.lastname: Piel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D004195:Disease Models, Animal; D004398:Dyneins / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D021381:Protein Transport; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D022161:Transport Vesicles / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020813:Receptor, trkB; D004398:Dyneins