Skip to content
BY-NC-ND 3.0 license Open Access Published by De Gruyter Open Access June 1, 2012

PTEN: A molecular target for neurodegenerative disorders

  • Azza Ismail EMAIL logo , Ke Ning , Abdulmonem Al-Hayani , Basil Sharrack and Mimoun Azzouz

Abstract

PTEN (phosphatase and tensin homologue deleted in chromosome 10) was first identified as a candidate tumour suppressor gene located on chromosome 10q23. It is considered as one of the most frequently mutated genes in human malignancies. Emerging evidence shows that the biological function of PTEN extends beyond its tumour suppressor activity. In the central nervous system PTEN is a crucial regulator of neuronal development, neuronal survival, axonal regeneration and synaptic plasticity. Furthermore, PTEN has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Recently increased attention has been focused on PTEN as a potential target for the treatment of brain injury and neurodegeneration. In this review we discuss the essential functions of PTEN in the central nervous system and its involvement in neurodegeneration.

[1] Datta S. R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery, Cell, 1997, 91, 231–241 http://dx.doi.org/10.1016/S0092-8674(00)80405-510.1016/S0092-8674(00)80405-5Search in Google Scholar

[2] Steck P. A., Pershouse M. A., Jasser S. A., Yung W.K., Lin H., Ligon A. H., et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers, Nat. Genet., 1997, 15, 356–362 http://dx.doi.org/10.1038/ng0497-35610.1038/ng0497-356Search in Google Scholar

[3] Li D. M., Sun H., TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta, Cancer Res., 1997, 57, 2124–2129 Search in Google Scholar

[4] Liaw D., Marsh D. J., Li J., Dahia P. L., Wang S. I., Zheng Z., et al., Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome, Nat. Genet., 1997, 16, 64–67 http://dx.doi.org/10.1038/ng0597-6410.1038/ng0597-64Search in Google Scholar

[5] Nelen M. R., van Staveren W. C., Peeters E. A., Hassel M. B., Gorlin R. J., Hamm H., et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease, Hum. Mol. Genet., 1997, 6, 1383–1387 http://dx.doi.org/10.1093/hmg/6.8.138310.1093/hmg/6.8.1383Search in Google Scholar

[6] Marsh D. J., Dahia P. L., Zheng Z., Liaw D., Parsons R., Gorlin R. J., et al., Germline mutations in PTEN are present in Bannayan-Zonana syndrome, Nat. Genet., 1997, 16, 333–334 http://dx.doi.org/10.1038/ng0897-33310.1038/ng0897-333Search in Google Scholar

[7] Lee J. O., Yang H., Georgescu M. M., Di Cristofano A., Maehama T., Shi Y., et al. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association, Cell, 1999, 99, 323–334 http://dx.doi.org/10.1016/S0092-8674(00)81663-310.1016/S0092-8674(00)81663-3Search in Google Scholar

[8] Wu X., Hepner K., Castelino-Prabhu S., Do D., Kaye M. B., Yuan X. J., et al. Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2, Proc. Natl. Acad. Sci. USA, 2000, 97, 4233–4238 http://dx.doi.org/10.1073/pnas.97.8.423310.1073/pnas.97.8.4233Search in Google Scholar PubMed PubMed Central

[9] Georgescu M. M., Kirsch K. H., Akagi T., Shishido T., Hanafusa H., The tumor-suppressor activity of PTEN is regulated by its carboxylterminal region, Proc. Natl. Acad. Sci. USA, 1999, 96, 10182–10187 http://dx.doi.org/10.1073/pnas.96.18.1018210.1073/pnas.96.18.10182Search in Google Scholar PubMed PubMed Central

[10] Vazquez F., Ramaswamy S., Nakamura N., Sellers W. R., Phosphorylation of the PTEN tail regulates protein stability and function, Mol. Cell. Biol., 2000, 20, 5010–5018 http://dx.doi.org/10.1128/MCB.20.14.5010-5018.200010.1128/MCB.20.14.5010-5018.2000Search in Google Scholar PubMed PubMed Central

[11] Maehama T., Dixon J. E., The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate, J. Biol. Chem., 1998, 273, 13375–13378 http://dx.doi.org/10.1074/jbc.273.22.1337510.1074/jbc.273.22.13375Search in Google Scholar PubMed

[12] Cantley L. C., The phosphoinositide 3-kinase pathway, Science, 2002, 296, 1655–1657 http://dx.doi.org/10.1126/science.296.5573.165510.1126/science.296.5573.1655Search in Google Scholar

[13] Kapeller R., Cantley L. C., Phosphatidylinositol 3-kinase, Bioessays, 1994, 16, 565–576 http://dx.doi.org/10.1002/bies.95016081010.1002/bies.950160810Search in Google Scholar

[14] Scheid M. P., Woodgett J. R., Unravelling the activation mechanisms of protein kinase B/Akt, FEBS Lett., 2003, 546, 108–112 http://dx.doi.org/10.1016/S0014-5793(03)00562-310.1016/S0014-5793(03)00562-3Search in Google Scholar

[15] Datta S. R., Brunet A., Greenberg M. E., Cellular survival: a play in three Akts, Genes Dev., 1999, 13, 2905–2927 http://dx.doi.org/10.1101/gad.13.22.290510.1101/gad.13.22.2905Search in Google Scholar

[16] Kandel E. S., Hay N., The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB, Exp. Cell Res., 1999, 253, 210–229 http://dx.doi.org/10.1006/excr.1999.469010.1006/excr.1999.4690Search in Google Scholar

[17] van Weeren P. C., de Bruyn K. M., de Vries-Smits A. M., van Lint J., Burgering B. M., Essential role for protein kinase B (PKB) in insulininduced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB, J. Biol. Chem., 1998, 273, 13150–13156 http://dx.doi.org/10.1074/jbc.273.21.1315010.1074/jbc.273.21.13150Search in Google Scholar

[18] Kops G. J., Burgering B. M., Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling, J. Mol. Med. 1999, 77, 656–665 http://dx.doi.org/10.1007/s00109990005010.1007/s001099900050Search in Google Scholar

[19] Cardone M. H., Roy N., Stennicke H. R., Salvesen G. S., Franke T. F., Stanbridge E., et al. Regulation of cell death protease caspase-9 by phosphorylation, Science, 1998, 282, 1318–1321 http://dx.doi.org/10.1126/science.282.5392.131810.1126/science.282.5392.1318Search in Google Scholar

[20] Kane L. P., Shapiro V. S., Stokoe D., Weiss A., Induction of NF-kappaB by the Akt/PKB kinase, Curr. Biol., 1999, 9, 601–604 http://dx.doi.org/10.1016/S0960-9822(99)80265-610.1016/S0960-9822(99)80265-6Search in Google Scholar

[21] Manning B. D., Cantley L. C., United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling, Biochem. Soc. Trans., 2003, 31, 573–578 http://dx.doi.org/10.1042/BST031057310.1042/bst0310573Search in Google Scholar PubMed

[22] Laplante M., Sabatini D. M., mTOR signaling at a glance, J. Cell Sci., 2009, 122, 3589–3594 http://dx.doi.org/10.1242/jcs.05101110.1242/jcs.051011Search in Google Scholar PubMed PubMed Central

[23] Wong E., Cuervo A. M., Autophagy gone awry in neurodegenerative diseases, Nat. Neurosci., 2010, 13, 805–811 http://dx.doi.org/10.1038/nn.257510.1038/nn.2575Search in Google Scholar PubMed PubMed Central

[24] Caccamo A., Majumder S., Deng J. J., Bai Y., Thornton F. B., Oddo S., Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability, J. Biol. Chem., 2009, 284, 27416–27424 http://dx.doi.org/10.1074/jbc.M109.03127810.1074/jbc.M109.031278Search in Google Scholar PubMed PubMed Central

[25] Malagelada C., Jin Z. H., Jackson-Lewis V., Przedborski S., Greene L. A., Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease, J. Neurosci., 2010, 30, 1166–1175 http://dx.doi.org/10.1523/JNEUROSCI.3944-09.201010.1523/JNEUROSCI.3944-09.2010Search in Google Scholar PubMed PubMed Central

[26] Bove J., Martinez-Vicente M., Vila M., Fighting neurodegeneration with rapamycin: mechanistic insights, Nat. Rev. Neurosci., 2011, 12, 437–452 http://dx.doi.org/10.1038/nrn306810.1038/nrn3068Search in Google Scholar PubMed

[27] Tamura M., Gu J., Matsumoto K., Aota S., Parsons R., Yamada K. M., Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN, Science, 1998, 280, 1614–1617 http://dx.doi.org/10.1126/science.280.5369.161410.1126/science.280.5369.1614Search in Google Scholar PubMed

[28] Podsypanina K., Ellenson L. H., Nemes A., Gu J., Tamura M., Yamada K. M., et al., Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems, Proc. Natl. Acad. Sci. USA, 1999, 96, 1563–1568 http://dx.doi.org/10.1073/pnas.96.4.156310.1073/pnas.96.4.1563Search in Google Scholar PubMed PubMed Central

[29] Ning K., Miller L. C., Laidlaw H. A., Burgess L. A., Perera N. M., Downes C. P., et al., A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic beta-cells, EMBO J., 2006, 25, 2377–2387 http://dx.doi.org/10.1038/sj.emboj.760111810.1038/sj.emboj.7601118Search in Google Scholar PubMed PubMed Central

[30] Ning K., Miller L. C., Laidlaw H. A., Watterson K. R., Gallagher J., Sutherland C., et al., Leptin-dependent phosphorylation of PTEN mediates actin restructuring and activation of ATP-sensitive K+ channels, J. Biol. Chem., 2009, 284, 9331–9340 http://dx.doi.org/10.1074/jbc.M80677420010.1074/jbc.M806774200Search in Google Scholar PubMed PubMed Central

[31] Weng L. P., Smith W. M., Brown J. L., Eng C., PTEN inhibits insulinstimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model, Hum. Mol. Genet., 2001, 10, 605–616 http://dx.doi.org/10.1093/hmg/10.6.60510.1093/hmg/10.6.605Search in Google Scholar PubMed

[32] Waite K. A., Eng C., Protean PTEN: form and function, Am. J. Hum. Genet., 2002, 70, 829–844 http://dx.doi.org/10.1086/34002610.1086/340026Search in Google Scholar

[33] Lachyankar M. B., Sultana N., Schonhoff C. M., Mitra P., Poluha W., Lambert S., et al., A role for nuclear PTEN in neuronal differentiation, J. Neurosci., 2000, 20, 1404–1413 10.1523/JNEUROSCI.20-04-01404.2000Search in Google Scholar

[34] Sano T., Lin H., Chen X., Langford L. A., Koul D., Bondy M. L., et al., Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis, Cancer Res., 1999, 59, 1820–1824 Search in Google Scholar

[35] Goberdhan D. C., Paricio N., Goodman E. C., Mlodzik M., Wilson C., Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway, Genes Dev., 1999, 13, 3244–3258 http://dx.doi.org/10.1101/gad.13.24.324410.1101/gad.13.24.3244Search in Google Scholar

[36] Huang H., Potter C. J., Tao W., Li D. M., Brogiolo W., Hafen E., et al., PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development, Development, 1999, 126, 5365–5372 10.1242/dev.126.23.5365Search in Google Scholar

[37] Di Cristofano A., Pesce B., Cordon-Cardo C., Pandolfi P. P., Pten is essential for embryonic development and tumour suppression, Nat. Genet., 1998,19, 348–355 http://dx.doi.org/10.1038/123510.1038/1235Search in Google Scholar

[38] Suzuki A., de la Pompa J. L., Stambolic V., Elia A. J., Sasaki T., del Barco Barrantes I., et al., High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice, Curr. Biol., 1998, 8, 1169–1178 http://dx.doi.org/10.1016/S0960-9822(07)00488-510.1016/S0960-9822(07)00488-5Search in Google Scholar

[39] Vasconsuelo A., Pronsato L., Ronda A. C., Boland R., Milanesi L., Role of 17β-estradiol and testosterone in apoptosis, Steroids, 2011, 76, 1223–1231 http://dx.doi.org/10.1016/j.steroids.2011.08.00110.1016/j.steroids.2011.08.001Search in Google Scholar PubMed

[40] Groszer M., Erickson R., Scripture-Adams D. D., Lesche R., Trumpp A., Zack J. A., et al., Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo, Science, 2001, 294, 2186–2189 http://dx.doi.org/10.1126/science.106551810.1126/science.1065518Search in Google Scholar PubMed

[41] Li L., Liu F., Salmonsen R. A., Turner T. K., Litofsky N. S., Di Cristofano A., et al., PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation, Mol. Cell. Neurosci., 2002, 20, 21–29 http://dx.doi.org/10.1006/mcne.2002.111510.1006/mcne.2002.1115Search in Google Scholar PubMed

[42] Marino S., Krimpenfort P., Leung C., van der Korput H. A. G. M., Trapman J., Camenisch I., et al., PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum, Development, 2002, 129, 3513–3522 10.1242/dev.129.14.3513Search in Google Scholar PubMed

[43] Backman S. A., Stambolic V., Suzuki A., Haight J., Elia A., Pretorius J., et al., Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease, Nat. Genet., 2001, 29, 396–403 http://dx.doi.org/10.1038/ng78210.1038/ng782Search in Google Scholar

[44] Kwon C. H., Zhu X., Zhang J., Knoop L. L., Tharp R., Smeyne R. J., et al., Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease, Nat. Genet., 2001, 29, 404–411 http://dx.doi.org/10.1038/ng78110.1038/ng781Search in Google Scholar

[45] Kyrylenko S., Roschier M., Korhonen P., Salminen A., Regulation of PTEN expression in neuronal apoptosis, Mol. Brain Res., 1999, 73, 198–202 http://dx.doi.org/10.1016/S0169-328X(99)00259-410.1016/S0169-328X(99)00259-4Search in Google Scholar

[46] Smith J. A., Zhang R., Varma A. K., Das A., Ray S. K., Banik N. L., Estrogen partially down-regulates PTEN to prevent apoptosis in VSC4.1 motoneurons following exposure to IFN-gamma, Brain Res., 2009, 1301, 163–170 http://dx.doi.org/10.1016/j.brainres.2009.09.01610.1016/j.brainres.2009.09.016Search in Google Scholar

[47] Xu J., Yeon J. E., Chang H., Tison G., Chen G. J., Wands J., et al., Ethanol impairs insulin-stimulated neuronal survival in the developing brain: role of PTEN phosphatase, J. Biol. Chem., 2003, 278, 26929–26937 http://dx.doi.org/10.1074/jbc.M30040120010.1074/jbc.M300401200Search in Google Scholar

[48] Gary D. S., Mattson M. P., PTEN regulates Akt kinase activity in hippocampal neurons and increases their sensitivity to glutamate and apoptosis, Neuromolecular Med., 2002, 2, 261–269 http://dx.doi.org/10.1385/NMM:2:3:26110.1385/NMM:2:3:261Search in Google Scholar

[49] Delgado-Esteban M., Martin-Zanca D., Andres-Martin L., Almeida A., Bolanos J. P., Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway, J. Neurochem., 2007, 102, 194–205 http://dx.doi.org/10.1111/j.1471-4159.2007.04450.x10.1111/j.1471-4159.2007.04450.xSearch in Google Scholar PubMed

[50] Zhao H., Shimohata T., Wang J. Q., Sun G., Schaal D. W., Sapolsky R. M., et al., Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats, J. Neurosci., 2005, 25, 9794–9806 http://dx.doi.org/10.1523/JNEUROSCI.3163-05.200510.1523/JNEUROSCI.3163-05.2005Search in Google Scholar PubMed PubMed Central

[51] Zhang Q.-G., Wu D.-N., Han D., Zhang G.-Y., Critical role of PTEN in the coupling between PI3K/Akt and JNK1/2 signaling in ischemic brain injury, FEBS Lett., 2007, 581, 495–505 http://dx.doi.org/10.1016/j.febslet.2006.12.05510.1016/j.febslet.2006.12.055Search in Google Scholar PubMed

[52] Ning K., Pei L., Liao M., Liu B., Zhang Y., Jiang W., et al., Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN, J. Neurosci. 2004, 24, 4052–4060 http://dx.doi.org/10.1523/JNEUROSCI.5449-03.200410.1523/JNEUROSCI.5449-03.2004Search in Google Scholar PubMed PubMed Central

[53] Liu B., Li L., Zhang Q., Chang N., Wang D., Shan Y., et al., Preservation of GABAA receptor function by PTEN inhibition protects against neuronal death in ischemic stroke, Stroke, 2010, 41, 1018–1026 http://dx.doi.org/10.1161/STROKEAHA.110.57901110.1161/STROKEAHA.110.579011Search in Google Scholar

[54] Cheung N. S., Choy M. S., Halliwell B., Teo T. S., Bay B. H., Lee A. Y. W., et al., Lactacystin-induced apoptosis of cultured mouse cortical neurons is associated with accumulation of PTEN in the detergent-resistant membrane fraction, Cell. Mol. Life Sci., 2004, 61, 1926–1934 http://dx.doi.org/10.1007/s00018-004-4127-710.1007/s00018-004-4127-7Search in Google Scholar

[55] Choy M. S., Bay B. H., Cheng H.-C., Cheung N. S., PTEN is recruited to specific microdomains of the plasma membrane during lactacystininduced neuronal apoptosis, Neurosci. Lett., 2006, 405, 120–125 http://dx.doi.org/10.1016/j.neulet.2006.06.03710.1016/j.neulet.2006.06.037Search in Google Scholar

[56] Zhang X., Li F., Bulloj A., Zhang Y.-W., Tong G., Zhang Z., et al., Tumorsuppressor PTEN affects tau phosphorylation, aggregation, and binding to microtubules, FASEB J., 2006, 20, 1272–1274 http://dx.doi.org/10.1096/fj.06-5721fje10.1096/fj.06-5721fjeSearch in Google Scholar

[57] Zhu Y., Hoell P., Ahlemeyer B., Sure U., Bertalanffy H., Krieglstein J., Implication of PTEN in production of reactive oxygen species and neuronal death in in vitro models of stroke and Parkinson’s disease, Neurochem. Int., 2007, 50, 507–516 http://dx.doi.org/10.1016/j.neuint.2006.10.01010.1016/j.neuint.2006.10.010Search in Google Scholar

[58] Park K. K., Liu K., Hu Y., Smith P. D., Wang C., Cai B., et al., Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway, Science, 2008, 322, 963–966 http://dx.doi.org/10.1126/science.116156610.1126/science.1161566Search in Google Scholar

[59] Liu K., Lu Y., Lee J. K., Samara R., Willenberg R., Sears-Kraxberger I., et al., PTEN deletion enhances the regenerative ability of adult corticospinal neurons, Nat. Neurosci., 2010, 13, 1075–1081 http://dx.doi.org/10.1038/nn.260310.1038/nn.2603Search in Google Scholar

[60] Jiang H., Guo W., Liang X., Rao Y., Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators, Cell, 2005, 120, 123–135 10.1016/S0092-8674(04)01258-9Search in Google Scholar

[61] Arevalo M.-A., Rodriguez-Tebar A., Activation of casein kinase II and inhibition of phosphatase and tensin homologue deleted on chromosome 10 phosphatase by nerve growth factor/p75NTR inhibit glycogen synthase kinase-3beta and stimulate axonal growth, Mol. Biol. Cell, 2006, 17, 3369–3377 http://dx.doi.org/10.1091/mbc.E05-12-114410.1091/mbc.e05-12-1144Search in Google Scholar PubMed PubMed Central

[62] Sun F., Park K. K., Belin S., Wang D., Lu T., Chen G., et al., Sustained axon regeneration induced by co-deletion of PTEN and SOCS3, Nature, 2011, 480, 372–375 http://dx.doi.org/10.1038/nature1059410.1038/nature10594Search in Google Scholar PubMed PubMed Central

[63] Leibinger M., Andreadaki A., Fischer D., Role of mTOR in neuroprotection and axon regeneration after inflammatory stimulation, Neurobiol. Dis., 2012, 46, 314–324 http://dx.doi.org/10.1016/j.nbd.2012.01.00410.1016/j.nbd.2012.01.004Search in Google Scholar

[64] Ning K., Drepper C., Valori C. F., Ahsan M., Wyles M., Higginbottom A., et al., PTEN depletion rescues axonal growth defect and improves survival in SMN-deficient motor neurons, Hum. Mol. Genet., 2010, 19, 3159–3168 http://dx.doi.org/10.1093/hmg/ddq22610.1093/hmg/ddq226Search in Google Scholar

[65] Perandones C., Costanzo R. V., Kowaljow V., Pivetta O. H., Carminatti H., Radrizzani M., Correlation between synaptogenesis and the PTEN phosphatase expression in dendrites during postnatal brain development, Mol. Brain Res., 2004, 128, 8–19 http://dx.doi.org/10.1016/j.molbrainres.2004.05.02110.1016/j.molbrainres.2004.05.021Search in Google Scholar

[66] Fraser M. M., Bayazitov I. T., Zakharenko S. S., Baker S. J., Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities, Neuroscience, 2008, 151, 476–488 http://dx.doi.org/10.1016/j.neuroscience.2007.10.04810.1016/j.neuroscience.2007.10.048Search in Google Scholar

[67] Xiong Q., Oviedo H. V., Trotman L. C., Zador A. M., PTEN regulation of local and long-range connections in mouse auditory cortex, J. Neurosci., 2012, 32, 1643–1652 http://dx.doi.org/10.1523/JNEUROSCI.4480-11.201210.1523/JNEUROSCI.4480-11.2012Search in Google Scholar

[68] Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., Binder L. I., Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology, Proc. Natl. Acad. Sci. USA, 1986, 83, 4913–4917 http://dx.doi.org/10.1073/pnas.83.13.491310.1073/pnas.83.13.4913Search in Google Scholar

[69] Stein T. D., Johnson J. A., Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways, J. Neuroscience, 2002, 22, 7380–7388 10.1523/JNEUROSCI.22-17-07380.2002Search in Google Scholar

[70] Wei W., Wang X., Kusiak J. W., Signaling events in amyloid betapeptide-induced neuronal death and insulin-like growth factor I protection, J. Biol. Chem., 2002, 277, 17649–17656 http://dx.doi.org/10.1074/jbc.M11170420010.1074/jbc.M111704200Search in Google Scholar

[71] Hanger D. P., Hughes K., Woodgett J. R., Brion J. P., Anderton B. H., Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase, Neurosci. Lett., 1992, 147, 58–62 http://dx.doi.org/10.1016/0304-3940(92)90774-210.1016/0304-3940(92)90774-2Search in Google Scholar

[72] Mandelkow E. M., Drewes G., Biernat J., Gustke N., Van Lint J., Vandenheede J. R., et al., Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau, FEBS Lett., 1992, 314, 315–321 http://dx.doi.org/10.1016/0014-5793(92)81496-910.1016/0014-5793(92)81496-9Search in Google Scholar

[73] Lovestone S., Reynolds C. H., Latimer D., Davis D. R., Anderton B. H., Gallo J. M., et al., Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells, Curr. Biol., 1994, 4, 1077–1086 http://dx.doi.org/10.1016/S0960-9822(00)00246-310.1016/S0960-9822(00)00246-3Search in Google Scholar

[74] Myers A., Holmans P., Marshall H., Kwon J., Meyer D., Ramic D., et al., Susceptibility locus for Alzheimer’s disease on chromosome 10, Science, 2000, 290, 2304–2305 http://dx.doi.org/10.1126/science.290.5500.230410.1126/science.290.5500.2304Search in Google Scholar

[75] Hamilton G., Samedi F., Knight J., Archer N., Foy C., Walter S., et al., Polymorphisms in the phosphate and tensin homolog gene are not associated with late-onset Alzheimer’s disease, Neurosci. Lett., 2006, 401, 77–80 http://dx.doi.org/10.1016/j.neulet.2006.03.02110.1016/j.neulet.2006.03.021Search in Google Scholar

[76] Griffin R. J., Moloney A., Kelliher M., Johnston J. A., Ravid R., Dockery P., et al., Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology, J. Neurochem., 2005, 93, 105–117 http://dx.doi.org/10.1111/j.1471-4159.2004.02949.x10.1111/j.1471-4159.2004.02949.xSearch in Google Scholar

[77] Kwak Y. D., Ma T., Diao S, Zhang X., Chen Y., Hsu J., et al., NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration, Mol. Neurodegener., 2010, 10, 49 http://dx.doi.org/10.1186/1750-1326-5-4910.1186/1750-1326-5-49Search in Google Scholar

[78] Sonoda Y., Mukai H., Matsuo K., Takahashi M., Ono Y., Maeda K., et al., Accumulation of tumor-suppressor PTEN in Alzheimer neurofibrillary tangles, Neurosci. Lett., 2010, 471, 20–24 http://dx.doi.org/10.1016/j.neulet.2009.12.07810.1016/j.neulet.2009.12.078Search in Google Scholar

[79] Kerr F., Rickle A., Nayeem N., Brandner S., Cowburn R. F., Lovestone S., PTEN, a negative regulator of PI3 kinase signalling, alters tau phosphorylation in cells by mechanisms independent of GSK-3, FEBS Lett., 2006, 580, 3121–3128 http://dx.doi.org/10.1016/j.febslet.2006.04.06410.1016/j.febslet.2006.04.064Search in Google Scholar

[80] Rickle A., Bogdanovic N., Volkmann I., Zhou X., Pei J.-J., Winblad B., et al., PTEN levels in Alzheimer’s disease medial temporal cortex, Neurochem. Int., 2006, 48, 114–123 http://dx.doi.org/10.1016/j.neuint.2005.08.01410.1016/j.neuint.2005.08.014Search in Google Scholar

[81] Rosen D. R., Siddique T., Patterson D., Figlewicz D. A., Sapp P., Hentati A., et al., Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, Nature, 1993, 362, 59–62 [Erratum appears in Nature, 1993, 364, 362] http://dx.doi.org/10.1038/362059a010.1038/362059a0Search in Google Scholar

[82] Sathasivam S., Shaw P. J., Apoptosis in amyotrophic lateral sclerosis—what is the evidence?, Lancet Neurol., 2005, 4, 500–509 http://dx.doi.org/10.1016/S1474-4422(05)70142-310.1016/S1474-4422(05)70142-3Search in Google Scholar

[83] Kiryu S., Morita N., Ohno K., Maeno H., Kiyama H., Regulation of mRNA expression involved in Ras and PKA signal pathways during rat hypoglossal nerve regeneration, Mol. Brain Res., 1995, 29, 147–156 http://dx.doi.org/10.1016/0169-328X(94)00241-610.1016/0169-328X(94)00241-6Search in Google Scholar

[84] Ito Y., Sakagami H., Kondo H., Enhanced gene expression for phosphatidylinositol 3-kinase in the hypoglossal motoneurons following axonal crush, Mol. Brain Res., 1996, 37, 329–332 http://dx.doi.org/10.1016/0169-328X(95)00329-Q10.1016/0169-328X(95)00329-QSearch in Google Scholar

[85] Namikawa K., Honma M., Abe K., Takeda M., Mansur K., Obata T., et al., Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration, J. Neurosci., 2000, 20, 2875–2886 10.1523/JNEUROSCI.20-08-02875.2000Search in Google Scholar

[86] Newbern J., Taylor A., Robinson M., Li L., Milligan C. E., Decreases in phosphoinositide-3-kinase/Akt and extracellular signal-regulated kinase 1/2 signaling activate components of spinal motoneuron death, J. Neurochem., 2005, 94, 1652–1665 http://dx.doi.org/10.1111/j.1471-4159.2005.03320.x10.1111/j.1471-4159.2005.03320.xSearch in Google Scholar PubMed

[87] Lunn J. S., Sakowski S. A., Kim B., Rosenberg A. A., Feldman E. L., Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration, Dev. Neurobiol., 2009, 69, 871–884 http://dx.doi.org/10.1002/dneu.2074710.1002/dneu.20747Search in Google Scholar PubMed PubMed Central

[88] Tolosa L., Mir M., Olmos G., Llado J., Vascular endothelial growth factor protects motoneurons from serum deprivation-induced cell death through phosphatidylinositol 3-kinase-mediated p38 mitogen-activated protein kinase inhibition, Neuroscience, 2009, 158, 1348–1355 http://dx.doi.org/10.1016/j.neuroscience.2008.10.06010.1016/j.neuroscience.2008.10.060Search in Google Scholar PubMed

[89] Tolosa L., Mir M., Asensio V. J., Olmos G., Llado J., Vascular endothelial growth factor protects spinal cord motoneurons against glutamateinduced excitotoxicity via phosphatidylinositol 3-kinase, J. Neurochem., 2008, 105, 1080–1090 http://dx.doi.org/10.1111/j.1471-4159.2007.05206.x10.1111/j.1471-4159.2007.05206.xSearch in Google Scholar PubMed

[90] Kaspar B. K., Llado J., Sherkat N., Rothstein J. D., Gage F. H., Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model, Science, 2003, 301, 839–842 http://dx.doi.org/10.1126/science.108613710.1126/science.1086137Search in Google Scholar PubMed

[91] Vincent A. M., Mobley B. C., Hiller A., Feldman E. L., IGF-I prevents glutamate-induced motor neuron programmed cell death, Neurobiol. Dis., 2004, 16, 407–416 http://dx.doi.org/10.1016/j.nbd.2004.03.00110.1016/j.nbd.2004.03.001Search in Google Scholar PubMed

[92] Manabe Y., Nagano I., Gazi M. S. A., Murakami T., Shiote M., Shoji M., et al., Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis, Apoptosis, 2002, 7, 329–334 http://dx.doi.org/10.1023/A:101612341303810.1023/A:1016123413038Search in Google Scholar

[93] Lim E., Lee S., Li E., Kim Y., Park S., Ghrelin protects spinal cord motoneurons against chronic glutamate-induced excitotoxicity via ERK1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3beta pathways, Exp. Neurol., 2011, 230, 114–122 http://dx.doi.org/10.1016/j.expneurol.2011.04.00310.1016/j.expneurol.2011.04.003Search in Google Scholar

[94] Kirby J., Ning K., Ferraiuolo L., Heath P. R., Ismail A., Kuo S.-W., et al., Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis, Brain, 2011, 134, 506–517 http://dx.doi.org/10.1093/brain/awq34510.1093/brain/awq345Search in Google Scholar

[95] Wagey R., Pelech S. L., Duronio V., Krieger C., Phosphatidylinositol 3-kinase: increased activity and protein level in amyotrophic lateral sclerosis, J. Neurochem., 1998, 71, 716–722 http://dx.doi.org/10.1046/j.1471-4159.1998.71020716.x10.1046/j.1471-4159.1998.71020716.xSearch in Google Scholar

[96] Dewil M., Lambrechts D., Sciot R., Shaw P. J., Ince P. G., Robberecht W., et al., Vascular endothelial growth factor counteracts the loss of phospho-Akt preceding motor neurone degeneration in amyotrophic lateral sclerosis, Neuropathol. Appl. Neurobiol., 2007, 33, 499–509 http://dx.doi.org/10.1111/j.1365-2990.2007.00850.x10.1111/j.1365-2990.2007.00850.xSearch in Google Scholar

[97] Warita H., Manabe Y., Murakami T., Shiro Y., Nagano I., Abe K., Early decrease of survival signal-related proteins in spinal motor neurons of presymptomatic transgenic mice with a mutant SOD1 gene, Apoptosis, 2001, 6, 345–352 http://dx.doi.org/10.1023/A:101133401880410.1023/A:1011334018804Search in Google Scholar

[98] Nagano I., Murakami T., Manabe Y., Abe K., Early decrease of survival factors and DNA repair enzyme in spinal motor neurons of presymptomatic transgenic mice that express a mutant SOD1 gene, Life Sci., 2002, 72, 541–548 http://dx.doi.org/10.1016/S0024-3205(02)02249-X10.1016/S0024-3205(02)02249-XSearch in Google Scholar

[99] Schapira A. H., Jenner P., Etiology and pathogenesis of Parkinson’s disease, Mov. Disord., 2011, 26, 1049–1055 http://dx.doi.org/10.1002/mds.2373210.1002/mds.23732Search in Google Scholar

[100] Chesselet M.-F., Richter F., Modelling of Parkinson’s disease in mice, Lancet Neurol., 2011, 10, 1108–1118 http://dx.doi.org/10.1016/S1474-4422(11)70227-710.1016/S1474-4422(11)70227-7Search in Google Scholar

[101] Valente E. M., Abou-Sleiman P. M., Caputo V., Muqit M. M. K., Harvey K., Gispert S., et al., Hereditary early-onset Parkinson’s disease caused by mutations in PINK1, Science, 2004, 304, 1158–1160 http://dx.doi.org/10.1126/science.109628410.1126/science.1096284Search in Google Scholar PubMed

[102] Greene L. A., Levy O., Malagelada C., Akt as a victim, villain and potential hero in Parkinson’s disease pathophysiology and treatment, Cell. Mol. Neurobiol., 31, 969–978 10.1007/s10571-011-9671-8Search in Google Scholar PubMed PubMed Central

[103] Timmons S., Coakley M. F., Moloney A. M., O’ Neill C., Akt signal transduction dysfunction in Parkinson’s disease, Neurosci. Lett., 2009, 467, 30–35 http://dx.doi.org/10.1016/j.neulet.2009.09.05510.1016/j.neulet.2009.09.055Search in Google Scholar

[104] Chen G., Bower K. A., Ma C., Fang S., Thiele C. J., Luo J., Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamineinduced neuronal death, FASEB J., 2004, 18, 1162–1164 http://dx.doi.org/10.1096/fj.03-0899com10.1096/fj.03-0899comSearch in Google Scholar

[105] Ries V., Henchcliffe C., Kareva T., Rzhetskaya M., Bland R., During M. J., et al., Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson’s disease, Proc. Natl. Acad. Sci. USA, 2006, 103, 18757–18762 http://dx.doi.org/10.1073/pnas.060640110310.1073/pnas.0606401103Search in Google Scholar

[106] Goedert M., Familial Parkinson’s disease. The awakening of alphasynuclein, Nature, 1997, 388, 232–233 http://dx.doi.org/10.1038/4076710.1038/40767Search in Google Scholar

[107] Heintz N., Zoghbi H., alpha-Synuclein — a link between Parkinson and Alzheimer diseases? Nat. Genet., 1997, 16, 325–327 http://dx.doi.org/10.1038/ng0897-32510.1038/ng0897-325Search in Google Scholar

[108] Hashimoto M., Bar-On P., Ho G., Takenouchi T., Rockenstein E., Crews L., et al., Beta-synuclein regulates Akt activity in neuronal cells. A possible mechanism for neuroprotection in Parkinson’s disease, J. Biol. Chem., 2004, 279, 23622–23629 http://dx.doi.org/10.1074/jbc.M31378420010.1074/jbc.M313784200Search in Google Scholar

[109] Shimoke K., Chiba H., Nerve growth factor prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced cell death via the Akt pathway by suppressing caspase-3-like activity using PC12 cells: relevance to therapeutical application for Parkinson’s disease, J. Neurosci. Res., 2001, 63, 402–409 http://dx.doi.org/10.1002/1097-4547(20010301)63:5<402::AID-JNR1035>3.0.CO;2-F10.1002/1097-4547(20010301)63:5<402::AID-JNR1035>3.0.CO;2-FSearch in Google Scholar

[110] Cookson M. R., Molecules that cause or prevent Parkinson’s disease, PLoS Biol., 2004, 2, e401 http://dx.doi.org/10.1371/journal.pbio.002040110.1371/journal.pbio.0020401Search in Google Scholar

[111] Kim R. H., Peters M., Jang Y., Shi W., Pintilie M., Fletcher G. C., et al., DJ-1, a novel regulator of the tumor suppressor PTEN, Cancer Cell, 2005, 7, 263–273 http://dx.doi.org/10.1016/j.ccr.2005.02.01010.1016/j.ccr.2005.02.010Search in Google Scholar

[112] Yang Y., Gehrke S., Haque M. E., Imai Y., Kosek J., Yang L., et al., Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling, Proc. Natl. Acad. Sci. USA, 2005, 102, 13670–13675 http://dx.doi.org/10.1073/pnas.050461010210.1073/pnas.0504610102Search in Google Scholar

[113] Diaz-Ruiz O., Zapata A., Shan L., Zhang Y., Tomac A. C., Malik N., et al., Selective deletion of PTEN in dopamine neurons leads to trophic effects and adaptation of striatal medium spiny projecting neurons, PLoS One, 2009, 4, e7027 http://dx.doi.org/10.1371/journal.pone.000702710.1371/journal.pone.0007027Search in Google Scholar PubMed PubMed Central

[114] Domanskyi A., Geissler C., Vinnikov I. A., Alter H., Schober A., Vogt M. A., et al., Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson’s disease models, FASEB J., 2011, 25, 2898–2910 http://dx.doi.org/10.1096/fj.11-18195810.1096/fj.11-181958Search in Google Scholar PubMed

[115] Ji S.-P., Zhang Y., Van Cleemput J., Jiang W., Liao M., Li L., et al., Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse, Nat. Med., 2006, 12, 324–329 http://dx.doi.org/10.1038/nm134910.1038/nm1349Search in Google Scholar PubMed

[116] Marsh D. J., Roth S., Lunetta K. L., Hemminki A., Dahia P. L., Sistonen P., et al., Exclusion of PTEN and 10q22–24 as the susceptibility locus for juvenile polyposis syndrome, Cancer Res., 1997, 57, 5017–5021 Search in Google Scholar

[117] Chang N., El-Hayek Y. H., Gomez E., Wan Q., Phosphatase PTEN in neuronal injury and brain disorders, Trends Neurosci., 2007, 30, 581–586 http://dx.doi.org/10.1016/j.tins.2007.08.00610.1016/j.tins.2007.08.006Search in Google Scholar PubMed

Published Online: 2012-6-1
Published in Print: 2012-6-1

© 2012 Versita Warsaw

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Downloaded on 25.4.2024 from https://www.degruyter.com/document/doi/10.2478/s13380-012-0018-9/html
Scroll to top button