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Published on: November 6, 2017
Calpain-mediated degradation of MDMx/MDM4 contributes to HIV-induced neuronal damage
Daniel J Colacurcio1, Alyssa Yeager, Dennis L Kolson
1Department of Pathology, School of Dental Medicine, University of Pennsylvania, 312 Levy Building, 240 South 40th Street, Philadelphia, PA 19104, United States.
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.
Insights
MDMx protein loss contributes to neuronal death in HIV-associated Neurocognitive Disorders (HAND). Restoring MDMx levels may protect neurons from HAND and other neurodegenerative diseases involving calpain activation.
Area of Science:
- Neuroscience
- Neuroimmunology
- Cell Biology
Background:
- HIV-associated Neurocognitive Disorders (HAND) involve neuronal damage linked to inflammation from activated brain macrophages/microglia.
- Aberrant neuronal cell cycle activation is implicated in determining cell fate under toxic conditions.
- Previous studies showed increased cell cycle proteins and decreased MDMx in HAND models.
Purpose of the Study:
- To investigate the role of MDMx in neuronal protection within the context of HAND.
- To determine if MDMx levels are altered in HAND patients.
- To elucidate the mechanism of MDMx regulation and its impact on neuronal survival.
Main Methods:
- Analysis of MDMx protein levels in the mid-frontal cortex of HAND patients.
- In vitro studies using primary rat neuroglial cultures treated with HIV-infected macrophage/microglia (HIV M/M) supernatants.
- Investigation of MDMx degradation pathways involving NMDA receptors and calpains.
- Overexpression and blocking of MDMx to assess its effect on neuronal survival.
- Assessment of calpain activity and its interaction with MDMx.
Main Results:
- MDMx protein levels were significantly reduced in the mid-frontal cortex of HAND patients.
- HIV M/M treatment induced NMDA receptor- and calpain-dependent degradation of MDMx, decreasing neuronal survival.
- Overexpression of MDMx provided partial protection against HIV M/M toxicity.
- MDMx was identified as a direct calpain substrate.
- Blocking MDMx activity caused neuronal death, which was reversible by calpain inhibition.
Conclusions:
- MDMx plays a crucial pro-survival role in neurons.
- Reduced MDMx levels contribute to neurodegeneration in HAND.
- Strategies aimed at stabilizing or increasing MDMx may offer neuroprotection in HAND.
- Targeting MDMx could be beneficial for other neurodegenerative diseases involving calpain activation.
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