title: HIV Glycoprotein Gp120 Impairs Fast Axonal Transport by Activating Tak1 Signaling Pathways.
abstract: Sensory neuropathies are the most common neurological complication of HIV. Of these, distal sensory polyneuropathy (DSP) is directly caused by HIV infection and characterized by length-dependent axonal degeneration of dorsal root ganglion (DRG) neurons. Mechanisms for axonal degeneration in DSP remain unclear, but recent experiments revealed that the HIV glycoprotein gp120 is internalized and localized within axons of DRG neurons. Based on these findings, we investigated whether intra-axonal gp120 might impair fast axonal transport (FAT), a cellular process critical for appropriate maintenance of the axonal compartment. Significantly, we found that gp120 severely impaired both anterograde and retrograde FAT. Providing a mechanistic basis for these effects, pharmacological experiments revealed an involvement of various phosphotransferases in this toxic effect, including members of mitogen-activated protein kinase pathways (Tak-1, p38, and c-Jun N-terminal Kinase (JNK)), inhibitor of kappa-B-kinase 2 (IKK2), and PP1. Biochemical experiments and axonal outgrowth assays in cell lines and primary cultures extended these findings. Impairments in neurite outgrowth in DRG neurons by gp120 were rescued using a Tak-1 inhibitor, implicating a Tak-1 mitogen-activated protein kinase pathway in gp120 neurotoxicity. Taken together, these observations indicate that kinase-based impairments in FAT represent a novel mechanism underlying gp120 neurotoxicity consistent with the dying-back degeneration seen in DSP. Targeting gp120-based impairments in FAT with specific kinase inhibitors might provide a novel therapeutic strategy to prevent axonal degeneration in DSP.
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA.|Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Berth
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: Mesnard-Hoaglin
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Center for Clinical and Translational Sciences, University of Illinois at Chicago, IL, USA.
authors.forename: Hajwa
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA.|Marine Biological Laboratory, Woods Hole, MA, USA.|Department of Systems Biology and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA USA.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA, USA.|Department of Biological Sciences, Howard Hughes Medical Institute, Hunter College, New York, NY, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Sapar
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA.|Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Morfini
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA stbrady@uic.edu.|Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Brady
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D001369:Axons / Q000187:drug effects*; D001596:Benzylamines; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D000080027:Cyclams; D049832:Decapodiformes; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D000071446:Neuronal Outgrowth / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D001596:Benzylamines; D003994:Bucladesine; D000080027:Cyclams; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D006571:Heterocyclic Compounds; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C088327:plerixafor
keywords: HIV; axonal transport; distal sensory polyneuropathy; gp120; kinesin; mitogen-activated protein kinase