Cited by 355Alzheimer's disease research and treatmentsCellular transport and secretionNeuroscience and Neuropharmacology Research

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Effects of PS1 Deficiency on Membrane Protein Trafficking in Neurons

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Naruse, Satoshi, Thinakaran, Gopal, Luo, Jin-Jun, Kusiak, John W, Tomita, Taisuke, Iwatsubo, Takeshi, Qian, Xiaozhong, Ginty, David D, Price, Donald L, Borchelt, David R, Wong, Philip C, Sisodia, Sangram S·1998·Neuron

DOI 10.1016/s0896-6273(00)80637-6

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Abstract

We have examined the trafficking and metabolism of the beta-amyloid precursor protein (APP), an APP homolog (APLP1), and TrkB in neurons that lack PS1. We report that PS1-deficient neurons fail to secrete Abeta, and that the rate of appearance of soluble APP derivatives in the conditioned medium is increased. Remarkably, carboxyl-terminal fragments (CTFs) derived from APP and APLP1 accumulate in PS1-deficient neurons. Hence, PS1 plays a role in promoting intramembrane cleavage and/or degradation of membrane-bound CTFs. Moreover, the maturation of TrkB and BDNF-inducible TrkB autophosphorylation is severely compromised in neurons lacking PS1. We conclude that PS1 plays an essential role in modulating trafficking and metabolism of a selected set of membrane and secretory proteins in neurons.

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BackgroundSelf-citation
Notch and presenilins in vertebrates and invertebrates: implications for neuronal development and degeneration
Selkoe, D. J. (2000) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(99)00054-9 · Cited by 66
Genetic and molecular aspects of Alzheimer's disease shed light on new mechanisms of transcriptional regulation
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“…et al. 2000; Pinnix et al. 2001; Sastre et al. 2001; Weidemann et al. 2002; Yu et al. 2001) APLP-1 & 2 ALID1 & ALID2 (Eggert et al. in press; Naruse et al. 1998; Scheinfeld et al. 2002) Notch NICD (De Strooper et al. 1999; Saxena et al. 2001) ErbB4 B4-ICD (Lee et al. 2002; Ni et al.…”
Background
Early Onset Alzheimer’s Disease and Oxidative Stress
Meraz‐Ríos, M. A., Franco-Bocanegra, D., Toral-Ríos, D., & Campos‐Peña, V. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/375968 · Cited by 65
“In addition to this function, presenilins directly or indirectly regulate the trafficking and metabolism of select membrane proteins in neurons [108].”
Background
A novel mechanism for the regulation of amyloid precursor protein metabolism
Chen, Q., Kimura, H., & Schubert, D. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200110151 · Cited by 63
“PS1 controls several aspects of APP metabolism (Sisodia, Amyloid precursor metabolism | Chen et al. 87 2000) and protein breakdown (Niwa et al., 1999; Katayama et al., 2000).”
New insight into protein glycosylation in the development of Alzheimer’s disease
Zhao, J., & Lang, M. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01617-5 · Cited by 63
“The overexpression of either wild-type or mutant PS1 disturbs glycoprotein processing within the Golgi [49], while the deficiency of PS leads to impaired secretion of Aβ proteins [50] (Fig.”
Background
Phosphorylation of Presenilin 1 at the Caspase Recognition Site Regulates Its Proteolytic Processing and the Progression of Apoptosis
Fluhrer, R., Friedlein, A., Haass, C., & Walter, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306653200 · Cited by 62
The −48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Aβ load in brain
Lambert, J.-C., Mann, D. M. A., Harris, J. M., Chartier-Harlin, M.-C., Cumming, A., Coates, J., Lemmon, H., StClair, D., Iwatsubo, T., & Lendon, C. (2001) · Journal of Medical Genetics · doi:10.1136/jmg.38.6.353 · Cited by 61
“Considerable research effort has been directed towards understanding the function of PS1 protein. Evidence suggests that it plays a role in cell trafficking”
Background
Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat
Mehler, M. F. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01705-7 · Cited by 61
Presenilins and γ-Secretase in Membrane Proteostasis
Oikawa, N., & Walter, J. (2019) · Cells · doi:10.3390/cells8030209 · Cited by 65
Familial Alzheimer Disease Presenilin-1 Mutations Alter the Active Site Conformation of γ-secretase
Chau, D.-M., Crump, C. J., Villa, J. C., Scheinberg, D. A., & Li, Y. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.300483 · Cited by 60
Localization of presenilin–nicastrin complexes and γ‐secretase activity to the trans‐Golgi network
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“…the trafficking of c-secretase components or substrates is supported by the finding that PS deficiency interferes with trafficking of the receptor tyrosine kinase TrkB to the plasma membrane, and modifies trafficking of APP and related family members (Naruse et al. 1998; Kaether et al. 2002).”
Background
Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis
Tamboli, I. Y., Prager, K., Thal, D. R., Thelen, K. M., Dewachter, I., Pietrzik, C. U., St. George-Hyslop, P., Sisodia, S. S., De Strooper, B., Heneka, M. T., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2635-08.2008 · Cited by 68
“…affect the subcellular trafficking of individual membrane proteins, including APP, TrkA, telencephalin, tyrosinase, and transferrin, but the underlying molecular mechanisms remain unclear (Naruse et al., 1998; Annaert et al., 2001; Wang et al., 2006; Zhang et al., 2006; Parks and Curtis, 2007).”
BackgroundSelf-citation
Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionarily conserved
Khandelwal, A., Chandu, D., Roe, C. M., Kopan, R., & Quatrano, R. S. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702038104 · Cited by 61
γ-Secretase: never more enigmatic
Sisodia, S. S., Annaert, W. G., Kim, S., & Strooper, B. D. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01987-1 · Cited by 58
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Abnormal blood vessel development in mice lacking presenilin-1
Nakajima, M., Yuasa, S., Ueno, M., Takakura, N., Koseki, H., & Shirasawa, T. (2003) · Mechanisms of Development · doi:10.1016/s0925-4773(03)00064-9 · Cited by 57
Microarray-based discovery of highly expressed olfactory mucosal genes: potential roles in the various functions of the olfactory system
Genter, M. B., Veldhoven, P. P. V., Jegga, A. G., Sakthivel, B., Kong, S., Stanley, K., Witte, D. P., Ebert, C. L., & Aronow, B. J. (2003) · Physiological Genomics · doi:10.1152/physiolgenomics.00117.2003 · Cited by 57
“, RAB3B (Rab3b); vesicleassociated membrane protein 2 (Vamp2); pantophysin (Pphn); and amyloid- (A4) precursor protein binding (Aplp2) (35, 47, 53, 75)], axonal guidance [e.”
Background
Presenilin/γ‐secretase activity regulates protein clearance from the endocytic recycling compartment
Zhang, M., Haapasalo, A., Kim, D. Y., Ingano, L. A. M., Pettingell, W. H., & Kovacs, D. M. (2006) · The FASEB Journal · doi:10.1096/fj.05-5531fje · Cited by 58
The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo
Mazzitelli, S., Xu, P., Ferrer, I., Davis, R. J., & Tournier, C. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4491-11.2011 · Cited by 57
“A similar phenotypic abnormality has been observed in cortical neurons defective in PS1 or expressing lossof-function variants (Naruse et al., 1998).”
Background
Notch1 Competes with the Amyloid Precursor Protein for γ-Secretase and Down-regulates Presenilin-1 Gene Expression
Lleó, A., Berezovska, O., Ramdya, P. P., Fukumoto, H., Raju, S., Shah, T. M., & Hyman, B. T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308480200 · Cited by 56
Subcellular Localization of Presenilins: Association with a Unique Membrane Pool in Cultured Cells
Kim, S., Lah, J. J., Thinakaran, G., Levey, A. I., & Sisodia, S. S. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0280 · Cited by 57
Self-citation
Presenilins in the Developing, Adult, and Aging Cerebral Cortex
Wines-Samuelson, M., & Shen, J. (2005) · The Neuroscientist · doi:10.1177/1073858405278922 · Cited by 54
The Value of Transgenic Models for the Study of Neurodegenerative Diseases
Price, D. L., Wong, P. C., Markowska, A. L., Lee, M. K., THINAKAREN, G., Cleveland, D. W., Sisodia, S. S., & Borchelt, D. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06920.x · Cited by 52
Self-citation
Subcellular Compartment and Molecular Subdomain of β-Amyloid Precursor Protein Relevant to the Aβ42-promoting Effects of Alzheimer Mutant Presenilin 2
Iwata, H., Tomita, T., Maruyama, K., & Iwatsubo, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007989200 · Cited by 52
Self-citation
Generation of intracellular domain of insulin receptor tyrosine kinase by γ-secretase
Kasuga, K., Kaneko, H., Nishizawa, M., Onodera, O., & Ikeuchi, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.06.022 · Cited by 52
Presenilins and the intramembrane proteolysis of proteins: facts and fiction
Strooper, B. D., & Annaert, W. G. (2001) · Nature Cell Biology · doi:10.1038/ncb1001-e221 · Cited by 52
Presenilins as therapeutic targets for the treatment of Alzheimer's disease
Golde, T. E., & Younkin, S. G. (2001) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(01)02064-0 · Cited by 49
Closing in on the Amyloid Cascade
Doms, R. W., & Huse, J. T. (2000) · Molecular Neurobiology · doi:10.1385/mn:22:1-3:081 · Cited by 50
“has been obtained on this subject (114,115).”
Synaptic contact number and size in stratum radiatum CA1 of APP/PS1ΔE9 transgenic mice
West, M. J., Bach, G., Søderman, A., & Jensen, J. L. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.01.009 · Cited by 48
Release of a membrane-bound death domain by γ-secretase processing of the p75NTR homolog NRADD
Gowrishankar, K., Zeidler, M. G., & Vincenz, C. (2004) · Journal of Cell Science · doi:10.1242/jcs.01263 · Cited by 49
Genetic studies in Alzheimer's disease
Tang, Y., & Gershon, E. S. (2003) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2003.5.1/yptang · Cited by 52
Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein
Lee, K.-W., Im, J., Song, J.-S., Lee, S. H., Lee, H.-J., Ha, H.-Y., Koh, J., Gwag, B. J., Yang, S.-D., Paik, S., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.09.011 · Cited by 48
The multiple paradoxes of presenilins
Checler, F. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00244.x · Cited by 48
“If the role of presenilins as a molecular transporter is privileged, it should be noted that Naruse et al. demonstrated nicely that deletion of presenilin 1 drastically impaired the neuronal intracellular transport of several proteins including bAPP (Naruse et al. 1998).”
Background
Presenilin 2 Expression in Neuronal Cells: Induction during Differentiation of Embryonic Carcinoma Cells
Culvenor, J. G., Evin, G. M., Cooney, M. A., Wardan, H., Sharples, R. A., Maher, F., Reed, G., Diehlmann, A., Weidemann, A., Beyreuther, K. T., et al. (2000) · Experimental Cell Research · doi:10.1006/excr.1999.4791 · Cited by 45
Presenilins and γ-Secretase Inhibitors Affect Intracellular Trafficking and Cell Surface Localization of the γ-Secretase Complex Components
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Self-citation
Partial Loss of Presenilin Impairs Age-Dependent Neuronal Survival in the Cerebral Cortex
Watanabe, H., Iqbal, M., Zheng, J., Wines-Samuelson, M., & Shen, J. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3261-14.2014 · Cited by 48
Loss of presenilin function causes Alzheimer's disease‐like neurodegeneration in the mouse
Chen, Q., Nakajima, A., Choi, S. H., Xiong, X., & Tang, Y. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21601 · Cited by 47
“Interestingly, the results from knockout studies have revealed that these genes have a gradient of importance in neuronal development, with PS1 the most essential (Zheng et al., 1996; Naruse et al., 1998; Herreman et al., 1999); thus, PS1-FAD is the most aggressive and has the earliest onset.”
Background
Presenilin 1 is involved in maturation and trafficking of N‐cadherin to the plasma membrane
Uemura, K., Kitagawa, N., Kohno, R., Kuzuya, A., Kageyama, T., Chonabayashi, K., Shibasaki, H., & Shimohama, S. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10753 · Cited by 47
“The majority of the early-onset familial form of Alzheimer’s disease (FAD) has been attributed to mutations in the presenilin 1 (PS1) gene (Rogaev et al., 1995; Sherrington et al., 1995; Haass, 1997).”
Background
Structural Biology of Presenilins and Signal Peptide Peptidases
Tomita, T., & Iwatsubo, T. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r113.463281 · Cited by 46
Self-citation
Comparative proteome analysis of differentially expressed proteins induced by K+ deficiency in Arabidopsis thaliana
Kang, J. G., Pyo, Y. J., Cho, J. W., & Cho, M. H. (2004) · PROTEOMICS · doi:10.1002/pmic.200400898 · Cited by 45
Presenilins and APP in Neuritic and Synaptic Plasticity: Implications for the Pathogenesis of Alzheimer's Disease
Chan, S. L., Furukawa, K., & Mattson, M. P. (2002) · NeuroMolecular Medicine · doi:10.1385/nmm:2:2:167 · Cited by 45
“This is supported by studies in which deletion of PS1 or its C. elegans homolog affects maturation of proteins such as APP, TrkB, Notch, and nicastrin (Naruse et al., 1998; Kim et al., 2001; Leem et al., 2002).”

Authors: Naruse, S., Thinakaran, G., Luo, J.-J., Kusiak, J. W., Tomita, T., Iwatsubo, T., Qian, X., Ginty, D. D., Price, D. L., Borchelt, D. R., Wong, P. C., & Sisodia, S. S.
Affiliations: University of Chicago (US)
Johns Hopkins University (US)
National Institute on Aging (US)
The University of Tokyo (JP)
Corresponding author: Sisodia, Sangram S
ORCID: Naruse, Satoshi
Thinakaran, Gopal
Luo, Jin-Jun
Kusiak, John W
Tomita, Taisuke
Iwatsubo, Takeshi
Qian, Xiaozhong
Ginty, David D
Borchelt, David R
Wong, Philip C
Sisodia, Sangram S
Venue: Neuron
Publisher: Elsevier BV
Published: 1998-11
Volume: 21
Issue: 5
Pages: 1213-1221
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/s0896-6273(00)80637-6
OpenAlex: W1994453752
Cited by: 355
References: 43
Citations by year: 2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 4 · 2013: 12 · 2012: 7
FWCI: 22.15
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 892 d)
Locations: Neuron (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: National Institute on Aging (1PO1 AG 14248, P50AG005146, P01AG014248, AG 05146)
National Institute of Neurological Disorders and Stroke (NS-20471)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: presenilin 1, APP, APLP1, amyloid-beta, carboxyl-terminal fragment, membrane protein trafficking, TrkB, brain-derived neurotrophic factor, autophosphorylation, intramembrane cleavage, protein degradation, Alzheimer's disease, neurons
MeSH terms: Alzheimer Disease, Animals, Cells, Cultured, Cerebral Cortex, Fetus, Membrane Proteins, Molecular Sequence Data, Neurons, Amyloid beta-Protein Precursor, Mice, Knockout, Mice, Presenilin-1

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Effects of PS1 Deficiency on Membrane Protein Trafficking in Neurons

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