Banker Gary

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  • Preprint
    Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin
    ( 2009-04-28) Morfini, Gerardo A. ; You, Yi-Mei ; Pollema, Sarah L. ; Kaminska, Agnieszka ; Liu, Katherine ; Yoshioka, Katsuji ; Bjorkblom, Benny ; Coffey, Eleanor T. ; Bagnato, Carolina ; Han, David ; Huang, Chun-Fang ; Banker, Gary ; Pigino, Gustavo F. ; Brady, Scott T.
    Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.
  • Article
    Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase
    (Public Library of Sceince, 2013-06-12) Morfini, Gerardo A. ; Bosco, Daryl A. ; Brown, Hannah ; Gatto, Rodolfo ; Kaminska, Agnieszka ; Song, Yuyu ; Molla, Linda ; Baker, Lisa ; Marangoni, M. Natalia ; Berth, Sarah ; Tavassoli, Ehsan ; Bagnato, Carolina ; Tiwari, Ashutosh ; Hayward, Lawrence J. ; Pigino, Gustavo F. ; Watterson, D. Martin ; Huang, Chun-Fang ; Banker, Gary ; Brown, Robert H. ; Brady, Scott T.
    Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.