The role of the Amyloid Precursor Protein mutations and PERKdependent signaling pathways in the pathogenesis of Alzheimer’s disease

Wioletta Rozpędek; Alicja Nowak; Dariusz Pytel; Dawid Lewko; J. Alan Diehl; Ireneusz Majsterek

doi:10.1515/fobio-2016-0005

Autor

Wioletta Rozpędek Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry
Alicja Nowak Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry
Dariusz Pytel Medical University of South Carolina, Hollings Cancer Center, Department of Biochemistry and Molecular Biology
Dawid Lewko Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry
J. Alan Diehl Medical University of South Carolina, Hollings Cancer Center, Department of Biochemistry and Molecular Biology
Ireneusz Majsterek Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry

DOI:

https://doi.org/10.1515/fobio-2016-0005

Słowa kluczowe:

Amyloid β, Endoplasmic Reticulum stress, Unfolded Protein Response, eIF2α, CHOP

Abstrakt

Choroba Alzheimera (ang. Alzheimer’s disease, AD) jest przewlekłą, najczęściej występującą, chorobą neurodegeneracyjną prowadzącą do nieodwracalnych zmian w strukturze, biochemii i funkcjach mózgu. Neurodegeneracja Ośrodkowego Układu Nerwowego (OUN) jest wynikiem odkładania toksycznych złogów amyloidu β (Aβ) w tkance nerwowej mózgu. Rozwój AD jest przyczyną skomplikowanych interakcji między podłożem genetycznym, a czynnikami biologicznymi, które aktywują złożone szlaki molekularne w przebiegu schorzenia. Za jedną z głównych przyczyn uważa się mutacje występujące w genie kodującym Prekursorowe białko amyloidu β (ang. Amyloid beta Precursor Protein, APP) zlokalizowane w pobliżu cięcia białka APP przez wysoce specyficzne sekretazy: α, β oraz γ. Generowanie toksycznej formy Aβ o długości 42-óch aminokwasów, odkładanego w tkance mózgowej jako płytki starcze, zachodzi poprzez drogę amyloidogenną, w której uczestniczą sekretazy β oraz γ. Na podłożu molekularnym główną przyczyną rozwoju choroby AD jest akumulacja błędnie sfałdowanych lub niesfałdowanych białek w lumen Retikulum Plazmatycznego (ang. Endoplasmic Reticulum, ER). Skutkuje to bezpośrednim wywołaniem stresu ER, który prowadzi do aktywacji kinazy PERK, a następnie fosforylacji eukariotycznego czynnika inicjacji translacji 2 (eIF2α). W rezultacie w komórce nerwowej inhibowana jest translacja większości białek oraz dochodzi do preferencyjnej translacji wyłącznie takich białek takich jak ATF4 (ang. Activating Transcriptor 4) oraz, wyniku długotrwałych warunków stresowych, CHOP (ang. CCAAT-enhancer-binding protein homologous protein). Nadekspresja białka CHOP prowadzi do wzmocnienia ekspresji genów kodujących: pro-apoptotyczne białka BH3 domain-only, GADD34 (ang. DNA damage-inducible protein, GADD34 oraz białko o aktywności oksydoreduktazy ER (ang. ER oxidoreductin 1α, ERO1α). W warunkach wysokiego stężenia białka CHOP zostaje osłabiona ekspresja genów kodujących anty-apoptotyczne białka Bcl-2. W rezultacie masa tkanki nerwowej mózgu ulega znaczącemu obniżeniu w wyniku postępującego procesu neurodegeneracji na drodze apoptotycznej śmierć komórkowej w przebiegu AD.

Pobrania

Statystyki pobrań niedostępne.

Bibliografia

Babusikova, E., Evinova, A., Jurecekova, J., Jesenak, M. & Dobrota, D. (2011) Alzheimer's Disease: Definition, Molecular and Genetic Factors. Advanced Understanding of Neurodegenerative Diseases. InTech.

Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D. & Jones, E. 2011. Alzheimer's disease. Lancet, 377(9770): 1019–1031.

Belyaev, N. D., Kellett, K. A., Beckett, C., Makova, N. Z., Revett, T. J., Nalivaeva, N. N., Hooper, N. M. & Turner, A. J. 2010. The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase-dependent pathway. The Journal of biological chemistry, 285(53): 41443–41454.

Blais, J. D., Filipenko, V., Bi, M., Harding, H. P., Ron, D., Koumenis, C., Wouters, B. G. & Bell, J. C. 2004. Activating transcription factor 4 is translationally regulated by hypoxic stress. Molecular and cellular biology, 24(17): 7469–7482.

Brown, M. K. & Naidoo, N. 2012. The endoplasmic reticulum stress response in aging and age-related diseases. Frontiers in physiology, 3: 263.

Brush, M. H., Weiser, D. C. & Shenolikar, S. 2003. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Molecular and cellular biology, 23(4): 1292–1303.

Chow, V. W., Mattson, M. P., Wong, P. C. & Gleichmann, M. 2010. An overview of APP processing enzymes and products. Neuromolecular medicine, 12(1): 1–12.

Cole, S. L. & Vassar, R. 2007. The Alzheimer's disease beta-secretase enzyme, BACE1. Molecular neurodegeneration, 2: 22.

Cooper, G. M. 2000. The cell: a molecular approach. ASM Press Sinauer Associates, Washington, D.C. Sunderland, Massachusetts.

Decock, M., Stanga, S., Octave, J. N., Dewachter, I., Smith, S. O., Constantinescu, S. N. & Kienlen-Campard, P. 2016. Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic Abeta Oligomers in Cells. Frontiers in aging neuroscience, 8: 107.

Devi, L. & Ohno, M. 2014. PERK mediates eIF2alpha phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease. Neurobiology of aging, 35(10): 2272–2281.

Dey, S., Baird, T. D., Zhou, D., Palam, L. R., Spandau, D. F. & Wek, R. C. 2010. Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. The Journal of biological chemistry, 285(43): 33165–33174.

Dislich, B. & Lichtenthaler, S. F. 2012. The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer's Disease and Beyond. Frontiers in physiology, 3: 8.

Doyle, K. M., Kennedy, D., Gorman, A. M., Gupta, S., Healy, S. J. & Samali, A. 2011. Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. Journal of cellular and molecular medicine, 15(10): 2025–2039.

Duran-Aniotz, C., Martinez, G. & Hetz, C. 2014. Memory loss in Alzheimer's disease: are the alterations in the UPR network involved in the cognitive impairment? Frontiers in aging neuroscience, 6: 8.

Ehehalt, R., Keller, P., Haass, C., Thiele, C. & Simons, K. 2003. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. The Journal of cell biology, 160(1): 113–123.

Elsby, R., Heiber, J. F., Reid, P., Kimball, S. R., Pavitt, G. D. & Barber, G. N. 2011. The alpha subunit of eukaryotic initiation factor 2B (eIF2B) is required for eIF2-mediated translational suppression of vesicular stomatitis virus. Journal of virology, 85(19): 9716–9725.

Feldman, D. E., Chauhan, V. & Koong, A. C. 2005. The unfolded protein response: a novel component of the hypoxic stress response in tumors. Molecular cancer research : MCR, 3(11): 597–605.

Fukumoto, H., Cheung, B. S., Hyman, B. T. & Irizarry, M. C. 2002. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Archives of neurology, 59(9): 1381–1389.

Guerreiro, R. J., Gustafson, D. R. & Hardy, J. 2012. The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE. Neurobiology of aging, 33(3): 437–456.

Harada, H., Tamaoka, A., Ishii, K., Shoji, S., Kametaka, S., Kametani, F., Saito, Y. & Murayama, S. 2006. Beta-site APP cleaving enzyme 1 (BACE1) is increased in remaining neurons in Alzheimer's disease brains. Neuroscience research, 54(1): 24–29.

Harding, H. P., Zhang, Y. & Ron, D. 1999. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 397(6716): 271–274.

Hardy, J. 1997. The Alzheimer family of diseases: many etiologies, one pathogenesis? Proceedings of the National Academy of Sciences of the United States of America, 94(6): 2095–2097.

Hattori, M., Fujiyama, A., Taylor, T. D., Watanabe, H., Yada, T., Park, H. S., Toyoda, A., Ishii, K., Totoki, Y., Choi, D. K., Groner, Y., Soeda, E., Ohki, M., Takagi, T., Sakaki, Y., Taudien, S., Blechschmidt, K., Polley, A., Menzel, U., Delabar, J., Kumpf, K., Lehmann, R., Patterson, D., Reichwald, K., Rump, A., Schillhabel, M., Schudy, A., Zimmermann, W., Rosenthal, A., Kudoh, J., Schibuya, K., Kawasaki, K., Asakawa, S., Shintani, A., Sasaki, T., Nagamine, K., Mitsuyama, S., Antonarakis, S. E., Minoshima, S., Shimizu, N., Nordsiek, G., Hornischer, K., Brant, P., Scharfe, M., Schon, O., Desario, A., Reichelt, J., Kauer, G., Blocker, H., Ramser, J., Beck, A., Klages, S., Hennig, S., Riesselmann, L., Dagand, E., Haaf, T., Wehrmeyer, S., Borzym, K., Gardiner, K., Nizetic, D., Francis, F., Lehrach, H., Reinhardt, R., Yaspo, M. L., Chromosome, m. and sequencing, c. 2000. The DNA sequence of human chromosome 21. Nature, 405(6784): 311–319.

Kimball, S. R. 1999. Eukaryotic initiation factor eIF2. The international journal of biochemistry & cell biology, 31(1): 25–29.

Krishnamoorthy, T., Pavitt, G. D., Zhang, F., Dever, T. E. & Hinnebusch, A. G. 2001. Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Molecular and cellular biology, 21(15): 5018–5030.

Kumar, S. & Walter, J. 2011. Phosphorylation of amyloid beta (Abeta) peptides - a trigger for formation of toxic aggregates in Alzheimer's disease. Aging, 3(8): 803–812.

Leissring, M. A., LaFerla, F. M., Callamaras, N. & Parker, I. 2001. Subcellular mechanisms of presenilin-mediated enhancement of calcium signaling. Neurobiology of disease, 8(3): 469–478.

Li, R., Lindholm, K., Yang, L. B., Yue, X., Citron, M., Yan, R., Beach, T., Sue, L., Sabbagh, M., Cai, H., Wong, P., Price, D. & Shen, Y. 2004. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients. Proceedings of the National Academy of Sciences of the United States of America, 101(10): 3632–3637.

Lichtenthaler, S. F. 2012. Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking. Current Alzheimer research, 9(2): 165–177.

Lorenzo, A. & Yankner, B. A. 1994. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proceedings of the National Academy of Sciences of the United States of America, 91(25): 12243–12247.

Ma, Y. & Hendershot, L. M. 2002. The mammalian endoplasmic reticulum as a sensor for cellular stress. Cell stress & chaperones, 7(2): 222–229.

Marciniak, S. J., Yun, C. Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H. P. & Ron, D. 2004. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes & development, 18(24): 3066–3077.

McCullough, K. D., Martindale, J. L., Klotz, L. O., Aw, T. Y. & Holbrook, N. J. 2001. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Molecular and cellular biology, 21(4): 1249–5129.

Moreno, J. A., Radford, H., Peretti, D., Steinert, J. R., Verity, N., Martin, M. G., Halliday, M., Morgan, J., Dinsdale, D., Ortori, C. A., Barrett, D. A., Tsaytler, P., Bertolotti, A., Willis, A. E., Bushell, M. & Mallucci, G. R. 2012. Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature, 485(7399): 507–511.

Nishitoh, H. 2012. CHOP is a multifunctional transcription factor in the ER stress response. Journal of biochemistry, 151(3): 217–219.

Oyadomari, S. & Mori, M. 2004. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell death and differentiation, 11(4): 381–389.

Pedrini, S., Thomas, C., Brautigam, H., Schmeidler, J., Ho, L., Fraser, P., Westaway, D., Hyslop, P. S., Martins, R. N., Buxbaum, J. D., Pasinetti, G. M., Dickstein, D. L., Hof, P. R., Ehrlich, M. E. & Gandy, S. 2009. Dietary composition modulates brain mass and solubilizable Abeta levels in a mouse model of aggressive Alzheimer's amyloid pathology. Molecular neurodegeneration, 4: 40.

Pennanen, C., Kivipelto, M., Tuomainen, S., Hartikainen, P., Hanninen, T., Laakso, M. P., Hallikainen, M., Vanhanen, M., Nissinen, A., Helkala, E. L., Vainio, P., Vanninen, R., Partanen, K. & Soininen, H. 2004. Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiology of aging, 25(3): 303–310.

Perez, R. G., Soriano, S., Hayes, J. D., Ostaszewski, B., Xia, W., Selkoe, D. J., Chen, X., Stokin, G. B. & Koo, E. H. 1999. Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42. The Journal of biological chemistry, 274(27): 18851–18856.

Pike, C. J., Walencewicz, A. J., Glabe, C. G. & Cotman, C. W. 1991. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain research, 563(1-2): 311–314.

Price, D. L., Sisodia, S. S. & Gandy, S. E. 1995. Amyloid beta amyloidosis in Alzheimer's disease. Current opinion in neurology, 8(4): 268–274.

Pytel, D., Seyb, K., Liu, M., Ray, S. S., Concannon, J., Huang, M., Cuny, G. D., Diehl, J. A. & Glicksman, M. A. 2014. Enzymatic Characterization of ER Stress-Dependent Kinase, PERK, and Development of a High-Throughput Assay for Identification of PERK Inhibitors. Journal of biomolecular screening, 19(7): 1024–1034.

Rutkowski, D. T. & Kaufman, R. J. 2004. A trip to the ER: coping with stress. Trends in cell biology, 14(1): 20–28.

Schonthal, A. H. 2012. Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica, 2012: 857516.

Sevier, C. S. & Kaiser, C. A. 2008. Ero1 and redox homeostasis in the endoplasmic reticulum. Biochimica et biophysica acta, 1783(4): 549–556.

Shamas-Din, A., Brahmbhatt, H., Leber, B. & Andrews, D. W. 2011. BH3-only proteins: Orchestrators of apoptosis. Biochimica et biophysica acta, 1813(4): 508–520.

Simmen, T., Lynes, E. M., Gesson, K. & Thomas, G. 2010. Oxidative protein folding in the endoplasmic reticulum: tight links to the mitochondria-associated membrane (MAM). Biochimica et biophysica acta, 1798(8): 1465–1473.

Sisodia, S. S. 1992. Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proceedings of the National Academy of Sciences of the United States of America, 89(13): 6075–6079.

Suragani, R. N., Ghosh, S., Ehtesham, N. Z. & Ramaiah, K. V. 2006. Expression and purification of the subunits of human translational initiation factor 2 (eIF2): phosphorylation of eIF2 alpha and beta. Protein expression and purification, 47(1): 225–233.

Szegezdi, E., Logue, S. E., Gorman, A. M. & Samali, A. 2006. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO reports, 7(9): 880–885.

Tabas, I. & Ron, D. 2011. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nature cell biology, 13(3): 184–190.

Tang, Y. P. & Gershon, E. S. 2003. Genetic studies in Alzheimer's disease. Dialogues in clinical neuroscience, 5(1): 17–26.

Tian, Y., Bassit, B., Chau, D. & Li, Y. M. 2010. An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production. Nature structural & molecular biology, 17(2): 151–158.

Vandewynckel, Y. P., Laukens, D., Geerts, A., Bogaerts, E., Paridaens, A., Verhelst, X., Janssens, S., Heindryckx, F. & Van Vlierberghe, H. 2013. The paradox of the unfolded protein response in cancer. Anticancer research, 33(11): 4683–4694.

Vassar, R. 2004. BACE1: the beta-secretase enzyme in Alzheimer's disease. Journal of molecular neuroscience: MN, 23(1-2): 105–114.

Vassar, R., Kovacs, D. M., Yan, R. & Wong, P. C. 2009. The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(41): 12787–12794.

Wagner, M. & Moore, D. D. 2011. Endoplasmic reticulum stress and glucose homeostasis. Current opinion in clinical nutrition and metabolic care, 14(4): 367–373.

Weggen, S. & Beher, D. 2012. Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease. Alzheimer's research & therapy, 4(2): 9.

Xu, C., Bailly-Maitre, B. & Reed, J. C. 2005. Endoplasmic reticulum stress: cell life and death decisions. The Journal of clinical investigation, 115(10): 2656–2564.

Zhou, L., Brouwers, N., Benilova, I., Vandersteen, A., Mercken, M., Van Laere, K., Van Damme, P., Demedts, D., Van Leuven, F., Sleegers, K., Broersen, K., Van Broeckhoven, C., Vandenberghe, R. & De Strooper, B. 2011. Amyloid precursor protein mutation E682K at the alternative beta-secretase cleavage beta'-site increases Abeta generation. EMBO molecular medicine, 3(5): 291–302.