title: Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders.
abstract: The advent of more effective antiretroviral therapies has reduced the frequency of HIV dementia, however the prevalence of milder HIV associated neurocognitive disorders [HAND] is actually rising. Neurodegenerative mechanisms in HAND might include toxicity by secreted HIV-1 proteins such as Tat, gp120 and Nef that could activate neuro-inflammatory pathways, block autophagy, promote excitotoxicity, oxidative stress, mitochondrial dysfunction and dysregulation of signaling pathways. Recent studies have shown that Tat could interfere with several signal transduction mechanisms involved in cytoskeletal regulation, cell survival and cell cycle re-entry. Among them, Tat has been shown to hyper-activate cyclin-dependent kinase [CDK] 5, a member of the Ser/Thr CDKs involved in cell migration, angiogenesis, neurogenesis and synaptic plasticity. CDK5 is activated by binding to its regulatory subunit, p35 or p39. For this manuscript we review evidence showing that Tat, via calcium dysregulation, promotes calpain-1 cleavage of p35 to p25, which in turn hyper-activates CDK5 resulting in abnormal phosphorylation of downstream targets such as Tau, collapsin response mediator protein-2 [CRMP2], doublecortin [DCX] and MEF2. We also present new data showing that Tat interferes with the trafficking of CDK5 between the nucleus and cytoplasm. This results in prolonged presence of CDK5 in the cytoplasm leading to accumulation of aberrantly phosphorylated cytoplasmic targets [e.g.: Tau, CRMP2, DCX] that impair neuronal function and eventually lead to cell death. Novel therapeutic approaches with compounds that block Tat mediated hyper-activation of CDK5 might be of value in the management of HAND.
authors.forename: Jerel Adam
authors.initials: JA
authors.lastname: Fields
authors.forename: Wilmar
authors.initials: W
authors.lastname: Dumaop
authors.forename: Leslie
authors.initials: L
authors.lastname: Crews
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Jeff
authors.initials: J
authors.lastname: Metcalf
authors.forename: Johnny
authors.initials: J
authors.lastname: He
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, 9500 Gilman Dr., MTF 348, La Jolla, CA 92093-0624, USA. emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D000089662:Doublecortin Protein; D004789:Enzyme Activation / Q000502:physiology*; D015658:HIV Infections / Q000150:complications* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D051379:Mice; D019965:Neurocognitive Disorders / Q000209:etiology* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D054322:tat Gene Products, Human Immunodeficiency Virus; D051360:Cyclin-Dependent Kinase 5; D002118:Calcium