Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin.
Selected vulnerability of neurons in Huntington's disease suggests that alterations occur in a cellular process that is particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal models of Huntington's disease (mouse and squid), but the molecular basis of this effect remains unknown. We found that polyQ-Htt inhibited FAT through a mechanism involving activation of axonal cJun N-terminal kinase (JNK). Accordingly, we observed increased activation of JNK in vivo in cellular and mouse models of Huntington's disease. Additional experiments indicated that the effects of polyQ-Htt on FAT were mediated by neuron-specific JNK3 and not by ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in Huntington's disease. Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provide a molecular basis for polyQ-Htt-induced inhibition of FAT.
Morfini
Gerardo A
GA
Department of Anatomy and Cell Biology, University of Illinois at Chicago, USA. gmorfini@uic.edu
You
Yi-Mei
YM
Pollema
Sarah L
SL
Kaminska
Agnieszka
A
Liu
Katherine
K
Yoshioka
Katsuji
K
Björkblom
Benny
B
Coffey
Eleanor T
ET
Bagnato
Carolina
C
Han
David
D
Huang
Chun-Fang
CF
Banker
Gary
G
Pigino
Gustavo
G
Brady
Scott T
ST
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D002460:Cell Line; D049832:Decapodiformes; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D010455:Peptides; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C097188:polyglutamine; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D016547:Kinesins