title: The viral protein gp120 decreases the acetylation of neuronal tubulin: potential mechanism of neurotoxicity.
abstract: The human immunodeficiency virus (HIV) envelope protein gp120 promotes axonal damage and neurite pruning, similar to that observed in HIV-positive subjects with neurocognitive disorders. Thus, gp120 has been used to examine molecular and cellular pathways underlying HIV-mediated neuronal dysfunction. Gp120 binds to tubulin beta III, a component of neuronal microtubules. Microtubule function, which modulates the homeostasis of neurons, is regulated by polymerization and post-translational modifications. Based on these considerations, we tested the hypothesis that gp120 induces dynamic instability of neuronal microtubules. We first observed that gp120 prevents the normal polymerization of tubulin in vitro. We then tested whether gp120 alters the post-translational modifications in tubulin by examining the ability of gp120 to change the levels of acetylated tubulin in primary rat neuronal cultures. Gp120 elicited a time-dependent decrease in tubulin acetylation that was reversed by Helix-A peptide, a compound that competitively displaces the binding of gp120 to neuronal microtubules. To determine whether post-translational modifications in tubulin also occur in vivo, we measured acetylated tubulin in the cerebral cortex of HIV transgenic rats (HIV-tg). We observed a decrease in tubulin acetylation in 5- and 9-month-old HIV-tg rats when compared to age-matched wild type. Neither changes in microglia morphology nor alterations in mRNA levels for interleukin-1β and tumor necrosis factor α were detected in 5-month-old animals. Our findings propose neuronal microtubule instability as a novel mechanism of HIV neurotoxicity, without evidence of enhanced inflammation.
authors.affiliation: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Washington, Washington, District of Columbia, USA.
authors.forename: Valeria
authors.identifier: 0000-0002-5640-3648
authors.initials: V
authors.lastname: Avdoshina
authors.affiliation: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Washington, Washington, District of Columbia, USA.
authors.forename: Seamus P
authors.initials: SP
authors.lastname: Caragher
authors.affiliation: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Washington, Washington, District of Columbia, USA.|Department of Pharmacology and Physiology, Georgetown University Washington, Washington, District of Columbia, USA.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Wenzel
authors.affiliation: Department of Regenerative Medicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Taraballi
authors.affiliation: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Washington, Washington, District of Columbia, USA.
authors.forename: Italo
authors.initials: I
authors.lastname: Mocchetti
authors.affiliation: National Toxicology Program Laboratory, National Institute of Environmental Health Science, Research Triangle Park, North Carolina, USA.
authors.forename: Gaylia Jean
authors.initials: GJ
authors.lastname: Harry
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology; D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology* / Q000633:toxicity*; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008870:Microtubules / Q000187:drug effects; D009474:Neurons / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D014404:Tubulin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015699:HIV Envelope Protein gp120; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha
keywords: 
  HAND
  ; HIV transgenic rats; Helix-A peptide; microglia; microtubules