title: Calpain-mediated degradation of MDMx/MDM4 contributes to HIV-induced neuronal damage.
abstract: Neuronal damage in HIV-associated Neurocognitive Disorders (HAND) has been linked to inflammation induced by soluble factors released by HIV-infected, and non-infected, activated macrophages/microglia (HIV M/M) in the brain. It has been suggested that aberrant neuronal cell cycle activation determines cell fate in response to these toxic factors. We have previously shown increased expression of cell cycle proteins such as E2F1 and phosphorylated pRb in HAND midfrontal cortex in vivo and in primary neurons exposed to HIV M/M supernatants in vitro. In addition, we have previously shown that MDMx (also referred to as MDM4), a negative regulator of E2F1, was decreased in the brain in a primate model of HIV-induced CNS neurodegeneration. Thus, we hypothesized that MDMx provides indirect neuroprotection from HIV-induced neurodegeneration in our in vitro model. In this report, we found significant reductions in MDMx protein levels in the mid-frontal cortex of patients with HAND. In addition, treatment of primary rat neuroglial cultures with HIV M/M led to NMDA receptor- and calpain-dependent degradation of MDMx and decreased neuronal survival, while overexpression of MDMx conferred partial protection from HIV M/M toxicity in vitro. Further, our results demonstrate that MDMx is a novel and direct calpain substrate. Finally, blocking MDMx activity led to neuronal death in vitro in the absence of toxic stimulus, which was reversed by calpain inhibition. Overall, our results indicate that MDMx plays a pro-survival role in neurons, and that strategies to stabilize and/or induce MDMx can provide neuroprotection in HAND and in other neurodegenerative diseases where calpain activation contributes to neuropathogenesis.
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, 312 Levy Building, 240 South 40th Street, Philadelphia, PA 19104, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Colacurcio
authors.forename: Alyssa
authors.initials: A
authors.lastname: Yeager
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kolson
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
authors.forename: Cagla
authors.initials: C
authors.lastname: Akay
mesh_terms: D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D018797:Cell Cycle Proteins; D016923:Cell Death; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000633:toxicity; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000821:virology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D017077:Culture Media, Conditioned; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D002154:Calpain
keywords: Calpain; Caspase; HIV-associated Neurocognitive Disorder; MDMx; Neuron; Neuroprotection