Rebuilding Synaptic Architecture in HIV-1 Associated Neurocognitive Disease

A Therapeutic Strategy Based on Modulation of Mixed Lineage Kinase

Harris A. Gelbard, Stephen Dewhurst, Sanjay B. Maggirwar, Michelle Kiebala, Oksana Polesskaya, Howard Eliot Gendelman

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Work from our laboratories has validated mixed lineage kinase type 3 (MLK3) as an enzyme pathologically activated in the CNS by human immunodeficiency virus 1 (HIV-1) neurotoxins. In this review, we discuss MLK3 activation in the context of the neuropathogenesis of HIV-1 associated neurocognitive deficits (HAND). We use findings from the literature to substantiate the neuropathologic relevance of MLK3 to neurodegenerative disease, with an emphasis on Parkinson's disease that shares a number of important phenotypic and neuropathologic characteristics with HAND. We discuss signal transduction pathways downstream from MLK3 activation, with an emphasis on their involvement in microglia and neurons in preclinical models of HAND. Finally, we make a case for pharmacologic intervention targeted at inhibition of MLK3 as a strategy to reverse HAND, in light of the fact that combination antiretroviral therapy, despite successfully managing systemic infection of HIV-1, has been largely unsuccessful in eradicating HAND.

Original languageEnglish (US)
Pages (from-to)392-398
Number of pages7
JournalNeurotherapeutics
Volume7
Issue number4
DOIs
StatePublished - Oct 1 2010

Fingerprint

HIV-1
Phosphotransferases
Therapeutics
Neurotoxins
Microglia
Neurodegenerative Diseases
Parkinson Disease
Signal Transduction
mitogen-activated protein kinase kinase kinase 11
Neurons
Enzymes
Infection

Keywords

  • HIV-1
  • HIV-1 associated neurocognitive disease (HAND)
  • Microglia
  • Mixed lineage kinase type 3
  • Neuroinflammation
  • Neurotrophins
  • Synapse
  • Tat

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Cite this

Rebuilding Synaptic Architecture in HIV-1 Associated Neurocognitive Disease : A Therapeutic Strategy Based on Modulation of Mixed Lineage Kinase. / Gelbard, Harris A.; Dewhurst, Stephen; Maggirwar, Sanjay B.; Kiebala, Michelle; Polesskaya, Oksana; Gendelman, Howard Eliot.

In: Neurotherapeutics, Vol. 7, No. 4, 01.10.2010, p. 392-398.

Research output: Contribution to journalArticle

Gelbard, Harris A. ; Dewhurst, Stephen ; Maggirwar, Sanjay B. ; Kiebala, Michelle ; Polesskaya, Oksana ; Gendelman, Howard Eliot. / Rebuilding Synaptic Architecture in HIV-1 Associated Neurocognitive Disease : A Therapeutic Strategy Based on Modulation of Mixed Lineage Kinase. In: Neurotherapeutics. 2010 ; Vol. 7, No. 4. pp. 392-398.
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