Pigino Gustavo F.

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Pigino
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Gustavo F.
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  • Preprint
    The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity
    ( 2008-04) LaPointe, Nichole E. ; Morfini, Gerardo A. ; Pigino, Gustavo F. ; Gaisina, Irina N. ; Kozikowski, Alan P. ; Binder, Lester I. ; Brady, Scott T.
    The neuropathology of Alzheimer’s disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dyneindependent FAT rates evaluated by video microscopy. While perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
  • Article
    Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2
    (Public Library of Science, 2017-12-20) Zamponi, Emiliano ; Buratti, Fiamma ; Cataldi, Gabriel ; Caicedo, Hector Hugo ; Song, Yuyu ; Jungbauer, Lisa M. ; LaDu, Mary J. ; Bisbal, Mariano ; Lorenzo, Lorenzo ; Ma, Jiyan ; Helguera, Pablo R. ; Morfini, Gerardo A. ; Brady, Scott T. ; Pigino, Gustavo F.
    Prion diseases include a number of progressive neuropathies involving conformational changes in cellular prion protein (PrPc) that may be fatal sporadic, familial or infectious. Pathological evidence indicated that neurons affected in prion diseases follow a dying-back pattern of degeneration. However, specific cellular processes affected by PrPc that explain such a pattern have not yet been identified. Results from cell biological and pharmacological experiments in isolated squid axoplasm and primary cultured neurons reveal inhibition of fast axonal transport (FAT) as a novel toxic effect elicited by PrPc. Pharmacological, biochemical and cell biological experiments further indicate this toxic effect involves casein kinase 2 (CK2) activation, providing a molecular basis for the toxic effect of PrPc on FAT. CK2 was found to phosphorylate and inhibit light chain subunits of the major motor protein conventional kinesin. Collectively, these findings suggest CK2 as a novel therapeutic target to prevent the gradual loss of neuronal connectivity that characterizes prion diseases.
  • Article
    Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases
    (Society for Neuroscience, 2011-07-06) Kanaan, Nicholas M. ; Morfini, Gerardo A. ; LaPointe, Nichole E. ; Pigino, Gustavo F. ; Patterson, Kristina R. ; Song, Yuyu ; Andreadis, Athena ; Fu, Yifan ; Brady, Scott T. ; Binder, Lester I.
    Aggregated filamentous forms of hyperphosphorylated tau (a microtubule-associated protein) represent pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. While axonal transport dysfunction is thought to represent a primary pathogenic factor in AD and other neurodegenerative diseases, the direct molecular link between pathogenic forms of tau and deficits in axonal transport remain unclear. Recently, we demonstrated that filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Here, we demonstrate that amino acids 2–18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway in axoplasms isolated from squid giant axons. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Importantly, immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity, an early marker of pathological tau. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT. Results from these studies reveal a novel role for tau in modulating axonal phosphotransferases and provide a molecular basis for a toxic gain-of-function associated with pathogenic forms of tau.
  • 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.