Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders.
Title | Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Fields, JAdam, Dumaop, W, Crews, L, Adame, A, Spencer, B, Metcalf, J, He, J, Rockenstein, E, Masliah, E |
Journal | Curr HIV Res |
Volume | 13 |
Issue | 1 |
Pagination | 43-54 |
Date Published | 2015 |
ISSN | 1873-4251 |
Keywords | Animals, Calcium, Cell Death, Cyclin-dependent kinase 5, Enzyme Activation, HIV Infections, HIV-1, Humans, Internal, Mice, neurocognitive disorders, Neurons, Phosphorylation, tat Gene Products, Human Immunodeficiency Virus |
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. |
DOI | 10.2174/1570162x13666150311164201 |
Alternate Journal | Curr HIV Res |
PubMed ID | 25760044 |
PubMed Central ID | PMC4455959 |
Grant List | U24 MH100929 / MH / NIMH NIH HHS / United States U01 MH083500 / MH / NIMH NIH HHS / United States R01 AG043384 / AG / NIA NIH HHS / United States MH062962 / MH / NIMH NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States MH5974 / MH / NIMH NIH HHS / United States R24 MH059745 / MH / NIMH NIH HHS / United States R01 MH062962 / MH / NIMH NIH HHS / United States F32 NS083426 / NS / NINDS NIH HHS / United States AG043384 / AG / NIA NIH HHS / United States U01 MH083506 / MH / NIMH NIH HHS / United States MH83506 / MH / NIMH NIH HHS / United States NS083426 / NS / NINDS NIH HHS / United States |