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Neuronal Cytoskeleton and HIV-Mediated Neurodegeneration

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Handbook of Neurotoxicity

Abstract

Human immunodeficiency virus (HIV) does not infect neurons, yet dendritic simplifications and loss of synapses are seen in different brain areas of people living with HIV. Nevertheless, the underlying causes of the pathological alterations observed in these individuals are poorly comprehended. HIV interactions with cells of the central nervous system occur through viral proteins, including gp120 and Tat. These proteins exhibit a potent neurotoxic effect on synapses. This chapter will briefly present new emerging concepts that link the ability of viral proteins to promote the degeneration of synapses by damaging the neuronal cytoskeleton.

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Abbreviations

AIDS:

Acquired immunodeficiency syndrome

ANI:

Asymptomatic neurocognitive impairment

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

cART:

Combination antiretroviral therapy

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

Gag:

Group-specific antigen

HAND:

HIV-associated neurocognitive disorder

HIV:

Human immunodeficiency virus-1

LTR:

Long terminal repeat

MAP 2:

MT-associated protein 2

MND:

Mild neurocognitive disorder

MTs:

Microtubules

Nef:

Negative regulating factor

NFs:

Neurofilaments

PLH:

People living with HIV

PTMs:

Posttranslational modifications

Rev.:

RNA splicing-regulator

Tat:

Transactivator of transcription

TUBB3:

Class III beta tubulin

Vif:

Viral infectivity factor

Vpr:

Viral protein R

Vpu:

Viral protein U

References

  • Avdoshina, V., Caragher, S. P., Wenzel, E. D., Taraballi, F., Mocchetti, I., & Harry, G. J. (2017). The viral protein gp120 decreases the acetylation of neuronal tubulin: Potential mechanism of neurotoxicity. Journal of Neurochemistry, 141, 606–613. https://doi.org/10.1111/jnc.14015

    Article  CAS  Google Scholar 

  • Avdoshina, V., Fields, J. A., Castellano, P., Dedoni, S., Palchik, G., Trejo, M., Adame, A., Rockenstein, E., Eugenin, E., Masliah, E., & Mocchetti, I. (2016). The HIV Protein gp120 alters mitochondrial dynamics in neurons. Neurotoxicity Research, 29, 583–593. https://doi.org/10.1007/s12640-016-9608-6

    Article  CAS  Google Scholar 

  • Avdoshina, V., Mahoney, M., Gilmore, S. F., Wenzel, E. D., Anderson, A., Letendre, S. L., Imamichi, T., Fischer, N. O., & Mocchetti, I. (2020). HIV influences microtubule associated protein-2: Potential marker of HIV-associated neurocognitive disorders. AIDS, 34, 979–988. https://doi.org/10.1097/QAD.0000000000002509

    Article  CAS  Google Scholar 

  • Avdoshina, V., Taraballi, F., Dedoni, S., Corbo, C., Paige, M., Saygideger Kont, Y., Uren, A., Tasciotti, E., & Mocchetti, I. (2016). Identification of a binding site of the human immunodeficiency virus envelope protein gp120 to neuronal-specific tubulin. Journal of Neurochemistry, 137, 287–298. https://doi.org/10.1111/jnc.13557

    Article  CAS  Google Scholar 

  • Bachis, A., Major, E. O., & Mocchetti, I. (2003). Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization. The Journal of Neuroscience, 23, 5715–5722.

    Article  CAS  Google Scholar 

  • Baird, F. J., & Bennett, C. L. (2013). Microtubule defects & neurodegeneration. Journal of Genetic Syndromes and Gene Therapy, 4, 203. https://doi.org/10.4172/2157-7412.1000203

    Article  CAS  Google Scholar 

  • Berth, S., Caicedo, H. H., Sarma, T., Morfini, G., & Brady, S. T. (2015). Internalization and axonal transport of the HIV glycoprotein gp120. ASN Neuro, 7. https://doi.org/10.1177/1759091414568186

  • Binder, L. I., Frankfurter, A., & Rebhun, L. I. (1985). The distribution of tau in the mammalian central nervous system. The Journal of Cell Biology, 101, 1371–1378.

    Article  CAS  Google Scholar 

  • Bruce-Keller, A. J., Chauhan, A., Dimayuga, F. O., Gee, J., Keller, J. N., & Nath, A. (2003). Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain. The Journal of Neuroscience, 23, 8417–8422.

    Article  CAS  Google Scholar 

  • Butler, T. R., Smith, K. J., Self, R. L., Braden, B. B., & Prendergast, M. A. (2011). Neurodegenerative effects of recombinant HIV-1 Tat(1-86) are associated with inhibition of microtubule formation and oxidative stress-related reductions in microtubule-associated protein-2(a,b). Neurochemical Research, 36, 819–828. https://doi.org/10.1007/s11064-011-0409-2

    Article  CAS  Google Scholar 

  • Cambray-Deakin, M. A., & Burgoyne, R. D. (1987). Posttranslational modifications of alpha-tubulin: Acetylated and detyrosinated forms in axons of rat cerebellum. The Journal of Cell Biology, 104, 1569–1574.

    Article  CAS  Google Scholar 

  • Cartelli, D., Ronchi, C., Maggioni, M. G., Rodighiero, S., Giavini, E., & Cappelletti, G. (2010). Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+ −induced neurodegeneration. Journal of Neurochemistry, 115, 247–258. https://doi.org/10.1111/j.1471-4159.2010.06924.x

    Article  CAS  Google Scholar 

  • Coles, C. H., & Bradke, F. (2015). Coordinating neuronal actin-microtubule dynamics. Current Biology, 25, R677–R691. https://doi.org/10.1016/j.cub.2015.06.020

    Article  CAS  Google Scholar 

  • Dehmelt, L., & Halpain, S. (2005). The MAP 2/Tau family of microtubule-associated proteins. Genome Biology, 6, 204. https://doi.org/10.1186/gb-2004-6-1-204

    Article  Google Scholar 

  • Del Valle, L., Croul, S., Morgello, S., Amini, S., Rappaport, J., & Khalili, K. (2000). Detection of HIV-1 Tat and JCV capsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy. Journal of Neurovirology, 6, 221–228.

    Article  Google Scholar 

  • Dixit, R., Ross, J. L., Goldman, Y. E., & Holzbaur, E. L. (2008). Differential regulation of dynein and kinesin motor proteins by tau. Science, 319, 1086–1089. https://doi.org/10.1126/science.1152993

    Article  CAS  Google Scholar 

  • Ensoli, B., Buonaguro, L., Barillari, G., Fiorelli, V., Gendelman, R., Morgan, R. A., Wingfield, P., & Gallo, R. C. (1993). Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. Journal of Virology, 67, 277–287.

    Article  CAS  Google Scholar 

  • Eugenin, E. A., Clements, J. E., Zink, M. C., & Berman, J. W. (2011). Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. The Journal of Neuroscience, 31, 9456–9465. 31/26/9456 [pii]. https://doi.org/10.1523/JNEUROSCI.1460-11.2011

    Article  CAS  Google Scholar 

  • Eugenin, E. A., King, J. E., Nath, A., Calderon, T. M., Zukin, R. S., Bennett, M. V. L., & Berman, J. W. (2007). HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proceedings of the National Academy of Sciences of the United States of America, 104, 3438–3443. https://doi.org/10.1073/pnas.0611699104

    Article  CAS  Google Scholar 

  • Fulga, T. A., Elson-Schwab, I., Khurana, V., Steinhilb, M. L., Spires, T. L., Hyman, B. T., & Feany, M. B. (2007). Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nature Cell Biology, 9, 139–148. https://doi.org/10.1038/ncb1528

    Article  CAS  Google Scholar 

  • Gelman, B. B. (2015). Neuropathology of HAND with suppressive antiretroviral therapy: Encephalitis and neurodegeneration reconsidered. Current HIV/AIDS Reports, 12, 272–279. https://doi.org/10.1007/s11904-015-0266-8

    Article  Google Scholar 

  • Hategan, A., Bianchet, M. A., Steiner, J., Karnaukhova, E., Masliah, E., Fields, A., Lee, M. H., Dickens, A. M., Haughey, N., Dimitriadis, E. K., & Nath, A. (2017). HIV Tat protein and amyloid-beta peptide form multifibrillar structures that cause neurotoxicity. Nature Structural & Molecular Biology, 24, 379–386. https://doi.org/10.1038/nsmb.3379

    Article  CAS  Google Scholar 

  • Haughey, N. J., Nath, A., Mattson, M. P., Slevin, J. T., & Geiger, J. D. (2001). HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. Journal of Neurochemistry, 78, 457–467.

    Article  CAS  Google Scholar 

  • Hirokawa, N., Shiomura, Y., & Okabe, S. (1988). Tau proteins: The molecular structure and mode of binding on microtubules. The Journal of Cell Biology, 107, 1449–1459.

    Article  CAS  Google Scholar 

  • Huang, Y., Paxton, W. A., Wolinsky, S. M., Neumann, A. U., Zhang, L., He, T., Kang, S., Ceradini, D., Jin, Z., Yazdanbakhsh, K., Kunstman, K., Erickson, D., Dragon, E., Landau, N. R., Phair, J., Ho, D. D., & Koup, R. A. (1996). The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nature Medicine, 2, 1240–1243.

    Article  CAS  Google Scholar 

  • Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X. F., & Yao, T. P. (2002). HDAC6 is a microtubule-associated deacetylase. Nature, 417, 455–458. https://doi.org/10.1038/417455a

    Article  CAS  Google Scholar 

  • Johnson, T. P., & Nath, A. (2016). Protocol for detection of HIV-Tat protein in cerebrospinal fluid by a Sandwich Enzyme-linked immunosorbent assay. Methods in Molecular Biology, 1354, 343–352. https://doi.org/10.1007/978-1-4939-3046-3_23

    Article  CAS  Google Scholar 

  • Khalil, M., Teunissen, C. E., Otto, M., Piehl, F., Sormani, M. P., Gattringer, T., Barro, C., Kappos, L., Comabella, M., Fazekas, F., Petzold, A., Blennow, K., Zetterberg, H., & Kuhle, J. (2018). Neurofilaments as biomarkers in neurological disorders. Nature Reviews. Neurology. https://doi.org/10.1038/s41582-018-0058-z

  • Lewis, S. A., Wang, D. H., & Cowan, N. J. (1988). Microtubule-associated protein MAP 2 shares a microtubule binding motif with tau protein. Science, 242, 936–939.

    Article  CAS  Google Scholar 

  • Li, W., Li, G., Steiner, J., & Nath, A. (2009). Role of Tat protein in HIV neuropathogenesis. Neurotoxicity Research, 16, 205–220. https://doi.org/10.1007/s12640-009-9047-8

    Article  CAS  Google Scholar 

  • Liu, Y., Jones, M., Hingtgen, C. M., Bu, G., Laribee, N., Tanzi, R. E., Moir, R. D., Nath, A., & He, J. J. (2000). Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. Nature Medicine, 6, 1380–1387. https://doi.org/10.1038/82199

    Article  CAS  Google Scholar 

  • Millecamps, S., & Julien, J. P. (2013). Axonal transport deficits and neurodegenerative diseases. Nature Reviews. Neuroscience, 14, 161–176. https://doi.org/10.1038/nrn3380

    Article  CAS  Google Scholar 

  • Ordonez, D. G., Lee, M. K., & Feany, M. B. (2018). Alpha-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton. Neuron, 97(108–124), e106. https://doi.org/10.1016/j.neuron.2017.11.036

    Article  CAS  Google Scholar 

  • Pacheco, A., & Gallo, G. (2016). Actin filament-microtubule interactions in axon initiation and branching. Brain Research Bulletin, 126, 300–310. https://doi.org/10.1016/j.brainresbull.2016.07.013

    Article  CAS  Google Scholar 

  • Rozzi, S. J., Avdoshina, V., Fields, J. A., & Mocchetti, I. (2018). Human immunodeficiency virus Tat impairs mitochondrial fission in neurons. Cell Death & Disease, 4, 8. https://doi.org/10.1038/s41420-017-0013-6

    Article  CAS  Google Scholar 

  • Sacktor, N. (2018). Changing clinical phenotypes of HIV-associated neurocognitive disorders. Journal of Neurovirology, 24, 141–145. https://doi.org/10.1007/s13365-017-0556-6

    Article  CAS  Google Scholar 

  • Sanchez, C., Diaz-Nido, J., & Avila, J. (2000). Phosphorylation of microtubule-associated protein 2 (MAP 2) and its relevance for the regulation of the neuronal cytoskeleton function. Progress in Neurobiology, 61, 133–168.

    Article  CAS  Google Scholar 

  • Song, Y., & Brady, S. T. (2015). Post-translational modifications of tubulin: Pathways to functional diversity of microtubules. Trends in Cell Biology, 25, 125–136. https://doi.org/10.1016/j.tcb.2014.10.004

    Article  CAS  Google Scholar 

  • Stern, J. L., Lessard, D. V., Hoeprich, G. J., Morfini, G. A., & Berger, C. L. (2017). Phosphoregulation of Tau modulates inhibition of kinesin-1 motility. Molecular Biology of the Cell, 28, 1079–1087. https://doi.org/10.1091/mbc.E16-10-0728

    Article  CAS  Google Scholar 

  • Teodorof, C., Divakar, S., Soontornniyomkij, B., Achim, C. L., Kaul, M., & Singh, K. K. (2014). Intracellular mannose binding lectin mediates subcellular trafficking of HIV-1 gp120 in neurons. Neurobiology of Disease, 69, 54–64. https://doi.org/10.1016/j.nbd.2014.05.002

    Article  CAS  Google Scholar 

  • Toggas, S. M., Masliah, E., Rockenstein, E. M., Rall, G. F., Abraham, C. R., & Mucke, L. (1994). Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature, 367, 188–193.

    Article  CAS  Google Scholar 

  • Vallee, R. B., Williams, J. C., Varma, D., & Barnhart, L. E. (2004). Dynein: An ancient motor protein involved in multiple modes of transport. Journal of Neurobiology, 58, 189–200. https://doi.org/10.1002/neu.10314

    Article  CAS  Google Scholar 

  • Verhey, K. J., & Hammond, J. W. (2009). Traffic control: Regulation of kinesin motors. Nature Reviews. Molecular Cell Biology, 10, 765–777. https://doi.org/10.1038/nrm2782

    Article  CAS  Google Scholar 

  • Watts, J. M., Dang, K. K., Gorelick, R. J., Leonard, C. W., Bess, J. W., Jr., Swanstrom, R., Burch, C. L., & Weeks, K. M. (2009). Architecture and secondary structure of an entire HIV-1 RNA genome. Nature, 460, 711–716. https://doi.org/10.1038/nature08237

    Article  CAS  Google Scholar 

  • Wenzel, E. D., Avdoshina, V., & Mocchetti, I. (2019). HIV-associated neurodegeneration: Exploitation of the neuronal cytoskeleton. Journal of Neurovirology, 25, 301–312. https://doi.org/10.1007/s13365-019-00737-y

    Article  CAS  Google Scholar 

  • Westermann, S., & Weber, K. (2003). Post-translational modifications regulate microtubule function. Nature Reviews. Molecular Cell Biology, 4, 938–947. https://doi.org/10.1038/nrm1260

    Article  CAS  Google Scholar 

  • Yuan, N. Y., & Kaul, M. (2019). Beneficial and adverse effects of cART affect neurocognitive function in HIV-1 infection: Balancing viral suppression against neuronal stress and injury. Journal of Neuroimmune Pharmacology. https://doi.org/10.1007/s11481-019-09868-9

  • Yuan, A., Rao, M. V., Veeranna, & Nixon, R. A. (2012). Neurofilaments at a glance. Journal of Cell Science, 125, 3257–3263. https://doi.org/10.1242/jcs.104729

    Article  CAS  Google Scholar 

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Acknowledgments

Support for this work was provided by HHS grants R01 NS079172 and R21 NS104000 to IM.

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Authors and Affiliations

  1. Interdisciplinary Program in Neuroscience and Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA

    Christy Agbey, Valeria Avdoshina & Italo Mocchetti

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  1. Christy Agbey
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  2. Valeria Avdoshina
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  3. Italo Mocchetti
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  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Agbey, C., Avdoshina, V., Mocchetti, I. (2022). Neuronal Cytoskeleton and HIV-Mediated Neurodegeneration. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_230

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