Molecular Neurobiology

, Volume 55, Issue 3, pp 1988–1997 | Cite as

DRAM Is Involved in Regulating Nucleoside Analog-Induced Neuronal Autophagy in a p53-Independent Manner

Article
First Online:
Received:
Accepted:
  • 250 Downloads

Abstract

The widespread use of combined anti-retroviral therapy (cART) has not decreased the prevalence of HIV-1-associated neurocognitive disorder (HAND), a type of neurodegenerative disease, even though cART effectively inhibits virus colonization in the central nervous system. Therefore, anti-retroviral agents cannot be fully excluded from the pathogenesis of HAND. Our previous study reported that long-term nucleoside analogue (NA) exposure induced mitochondrial toxicity in the cortical neurons of HAND patients and mice, but the exact mechanism of NA-associated neurotoxicity has remained unclear. Alteration of autophagy can result in protein aggregation and the accumulation of dysfunctional organelles, which are hallmarks of some neurodegenerative diseases. In this study, we first found increased autophagy in cortical autopsy specimens of AIDS patients. We then found that a low dose of NAs could stimulate autophagy in primary cultured neurons, while a high dose of NAs could induce only neuronal apoptosis. The level of NA-induced Bcl-2 and Bax expressions determined whether neuronal autophagy or apoptosis occurred. Furthermore, the level of NA-induced neuronal apoptosis correlated with the dysfunction of cellular DNA polymerase gamma. Damage-regulated autophagy modulator (DRAM) overexpression was also involved in NA-induced neuronal autophagy. p53 played a role in the regulation of NA-induced neuronal apoptosis, but its role in NA-associated neuronal autophagy was uncertain. Our results suggest that DRAM is involved in the regulation of NA-induced neuronal autophagy in a p53-independent manner. Further research is needed to investigate the underlying mechanism.

Keywords

Autophagy Apoptosis DRAM Neuronal toxicity Nucleoside analog 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81371399, 81571178, and 81272266), the Capital Health Development Research Projects (Capital Development 2014-1-1151), and the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges under Beijing Municipality (IDHT20150502).

Author’s Contribution

Yulin Zhang and Dexi Chen planned the study and prepared the figures, Junqi Shan and Bishi Wang performed the laboratory tests, and Luxin Qiao and Ziyun Gao prepared the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Mothobi NZ, Brew BJ (2012) Neurocognitive dysfunction in the highly active antiretroviral therapy era. Curr Opin Infect Dis 25(1):4–9. doi: 10.1097/QCO.0b013e32834ef586 CrossRefPubMedGoogle Scholar
  2. 2.
    Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA et al (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. Journal of neurovirology 17(1):3–16. doi: 10.1007/s13365-010-0006-1 CrossRefPubMedGoogle Scholar
  3. 3.
    Kandanearatchi A, Williams B, Everall IP (2003) Assessing the efficacy of highly active antiretroviral therapy in the brain. Brain Pathol 13(1):104–110CrossRefPubMedGoogle Scholar
  4. 4.
    Tozzi V, Balestra P, Galgani S, Narciso P, Sampaolesi A, Antinori A, Giulianelli M, Serraino D et al (2001) Changes in neurocognitive performance in a cohort of patients treated with HAART for 3 years. J Acquir Immune Defic Syndr 28(1):19–27CrossRefPubMedGoogle Scholar
  5. 5.
    Zhang Y, Wang M, Li H, Zhang H, Shi Y, Wei F, Liu D, Liu K et al (2012) Accumulation of nuclear and mitochondrial DNA damage in the frontal cortex cells of patients with HIV-associated neurocognitive disorders. Brain Res 1458:1–11. doi: 10.1016/j.brainres.2012.04.001 CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang Y, Song F, Gao Z, Ding W, Qiao L, Yang S, Chen X, Jin R et al (2014) Long-term exposure of mice to nucleoside analogues disrupts mitochondrial DNA maintenance in cortical neurons. PLoS One 9(1):e85637. doi: 10.1371/journal.pone.0085637 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lim Y, Cho H, Kim EK (2016) Brain metabolism as a modulator of autophagy in neurodegeneration. Brain Res. doi: 10.1016/j.brainres.2016.02.049 Google Scholar
  8. 8.
    Alirezaei M, Kiosses WB, Fox HS (2008) Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity. Autophagy 4(7):963–966CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Dever SM, Rodriguez M, Lapierre J, Costin BN, El-Hage N (2015) Differing roles of autophagy in HIV-associated neurocognitive impairment and encephalitis with implications for morphine co-exposure. Front Microbiol 6:653. doi: 10.3389/fmicb.2015.00653 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhang Y, Shi Y, Qiao L, Sun Y, Ding W, Zhang H, Li N, Chen D (2012) Sigma-1 receptor agonists provide neuroprotection against gp120 via a change in bcl-2 expression in mouse neuronal cultures. Brain Res 1431:13–22. doi: 10.1016/j.brainres.2011.10.053 CrossRefPubMedGoogle Scholar
  11. 11.
    Shi Y, Han Y, Xie F, Wang A, Feng X, Li N, Guo H, Chen D (2015) ASPP2 enhances oxaliplatin (L-OHP)-induced colorectal cancer cell apoptosis in a p53-independent manner by inhibiting cell autophagy. J Cell Mol Med 19(3):535–543. doi: 10.1111/jcmm.12435 CrossRefPubMedGoogle Scholar
  12. 12.
    Lin TN, He YY, Wu G, Khan M, Hsu CY (1993) Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke; a journal of cerebral circulation 24(1):117–121CrossRefGoogle Scholar
  13. 13.
    Mah LY, O'Prey J, Baudot AD, Hoekstra A, Ryan KM (2012) DRAM-1 encodes multiple isoforms that regulate autophagy. Autophagy 8(1):18–28. doi: 10.4161/auto.8.1.18077 CrossRefPubMedGoogle Scholar
  14. 14.
    Thorburn A (2008) Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis : an international journal on programmed cell death 13(1):1–9. doi: 10.1007/s10495-007-0154-9 CrossRefGoogle Scholar
  15. 15.
    Zhou F, Yang Y, Xing D (2011) Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis. FEBS J 278(3):403–413. doi: 10.1111/j.1742-4658.2010.07965.x CrossRefPubMedGoogle Scholar
  16. 16.
    Gui YX, Xu ZP, Lv W, Zhao JJ, Hu XY (2015) Evidence for polymerase gamma, POLG1 variation in reduced mitochondrial DNA copy number in Parkinson’s disease. Parkinsonism Relat Disord 21(3):282–286. doi: 10.1016/j.parkreldis.2014.12.030 CrossRefPubMedGoogle Scholar
  17. 17.
    Ylonen S, Ylikotila P, Siitonen A, Finnila S, Autere J, Majamaa K (2013) Variations of mitochondrial DNA polymerase gamma in patients with Parkinson’s disease. J Neurol 260(12):3144–3149. doi: 10.1007/s00415-013-7132-7 CrossRefPubMedGoogle Scholar
  18. 18.
    Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O et al (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126(1):121–134. doi: 10.1016/j.cell.2006.05.034 CrossRefPubMedGoogle Scholar
  19. 19.
    Dagan T, Sable C, Bray J, Gerschenson M (2002) Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities: what is the evidence? Mitochondrion 1(5):397–412CrossRefPubMedGoogle Scholar
  20. 20.
    Obiako OR, Abdu-Aguye I, Ogunniyi A (2011) Effect of stavudine-based antiretroviral therapy on the severity of polyneuropathy in HIV/AIDS patients: a preliminary report from Zaria, northern Nigeria. West Afr J Med 30(5):354–358PubMedGoogle Scholar
  21. 21.
    Dragovic G, Jevtovic D (2012) The role of nucleoside reverse transcriptase inhibitors usage in the incidence of hyperlactatemia and lactic acidosis in HIV/AIDS patients. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 66(4):308–311. doi: 10.1016/j.biopha.2011.09.016 CrossRefGoogle Scholar
  22. 22.
    Li M, Mislak AC, Foli Y, Agbosu E, Bose V, Bhandari S, Szymanski MR, Shumate CK et al (2016) DNA polymerase-gamma R953C mutant is associated with ART-induced mitochondrial toxicity. Antimicrob Agents Chemother. doi: 10.1128/AAC.00976-16 Google Scholar
  23. 23.
    Khatami M, Heidari MM, Mansouri R, Mousavi F (2015) The POLG polyglutamine tract variants in Iranian patients with multiple sclerosis. Iranian journal of child neurology 9(1):37–41PubMedPubMedCentralGoogle Scholar
  24. 24.
    Kukreja L, Kujoth GC, Prolla TA, Van Leuven F, Vassar R (2014) Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer’s disease. Mol Neurodegener 9:16. doi: 10.1186/1750-1326-9-16 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Perier C, Bender A, Garcia-Arumi E, Melia MJ, Bove J, Laub C, Klopstock T, Elstner M et al (2013) Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms. Brain : a journal of neurology 136(Pt 8):2369–2378. doi: 10.1093/brain/awt196 CrossRefGoogle Scholar
  26. 26.
    Kizilarslanoglu MC, Ulger Z (2015) Role of autophagy in the pathogenesis of Alzheimer disease. Turkish journal of medical sciences 45(5):998–1003CrossRefPubMedGoogle Scholar
  27. 27.
    Gan-Or Z, Dion PA, Rouleau GA (2015) Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11(9):1443–1457. doi: 10.1080/15548627.2015.1067364 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Meulendyke KA, Croteau JD, Zink MC (2014) HIV life cycle, innate immunity and autophagy in the central nervous system. Curr Opin HIV AIDS 9(6):565–571. doi: 10.1097/COH.0000000000000106 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rey-Jurado E, Riedel CA, Gonzalez PA, Bueno SM, Kalergis AM (2015) Contribution of autophagy to antiviral immunity. FEBS Lett 589(22):3461–3470. doi: 10.1016/j.febslet.2015.07.047 CrossRefPubMedGoogle Scholar
  30. 30.
    Saribas AS, Khalili K, Sariyer IK (2015) Dysregulation of autophagy by HIV-1 Nef in human astrocytes. Cell Cycle 14(18):2899–2904. doi: 10.1080/15384101.2015.1069927 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Spector SA, Zhou D (2008) Autophagy: an overlooked mechanism of HIV-1 pathogenesis and neuroAIDS? Autophagy 4(5):704–706CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Gougeon ML, Piacentini M (2009) New insights on the role of apoptosis and autophagy in HIV pathogenesis. Apoptosis : an international journal on programmed cell death 14(4):501–508. doi: 10.1007/s10495-009-0314-1 CrossRefGoogle Scholar
  33. 33.
    Fields J, Dumaop W, Eleuteri S, Campos S, Serger E, Trejo M, Kosberg K, Adame A et al (2015) HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(5):1921–1938. doi: 10.1523/JNEUROSCI.3207-14.2015 CrossRefGoogle Scholar
  34. 34.
    El-Hage N, Rodriguez M, Dever SM, Masvekar RR, Gewirtz DA, Shacka JJ (2015) HIV-1 and morphine regulation of autophagy in microglia: limited interactions in the context of HIV-1 infection and opioid abuse. J Virol 89(2):1024–1035. doi: 10.1128/JVI.02022-14 CrossRefPubMedGoogle Scholar
  35. 35.
    Sanchez AB, Varano GP, de Rozieres CM, Maung R, Catalan IC, Dowling CC, Sejbuk NE, Hoefer MM et al (2016) Antiretrovirals, methamphetamine, and HIV-1 envelope protein gp120 compromise neuronal energy homeostasis in association with various degrees of synaptic and neuritic damage. Antimicrob Agents Chemother 60(1):168–179. doi: 10.1128/AAC.01632-15 CrossRefGoogle Scholar
  36. 36.
    Clavier A, Rincheval-Arnold A, Colin J, Mignotte B, Guenal I (2016) Apoptosis in drosophila: which role for mitochondria? Apoptosis : an international journal on programmed cell death 21(3):239–251. doi: 10.1007/s10495-015-1209-y CrossRefGoogle Scholar
  37. 37.
    Heath-Engel HM, Chang NC, Shore GC (2008) The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family. Oncogene 27(50):6419–6433. doi: 10.1038/onc.2008.309 CrossRefPubMedGoogle Scholar
  38. 38.
    Booth LA, Tavallai S, Hamed HA, Cruickshanks N, Dent P (2014) The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell Signal 26(3):549–555. doi: 10.1016/j.cellsig.2013.11.028 CrossRefPubMedGoogle Scholar
  39. 39.
    Wang DB, Kinoshita C, Kinoshita Y, Morrison RS (2014) p53 and mitochondrial function in neurons. Biochim Biophys Acta 1842(8):1186–1197. doi: 10.1016/j.bbadis.2013.12.015 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of NeurosurgerySecond Affiliated Hospital of Nanchang UniversityNanchangChina
  2. 2.The Fourth General Surgery Division, Shandong Cancer Hospital, School of Medicine and Life SciencesUniversity of Jinan-Shandong Academy of Medical SciencesJinanChina
  3. 3.Department of Infectious Diseases, Beijing Institute of HepatologyCapital Medical University affiliated Beijing You An HospitalBeijingChina

Personalised recommendations