Potential molecular link between the β-amyloid precursor protein (APP) and hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme in Lesch-Nyhan disease and cancer

Khue Vu Nguyen; Khue Vu Nguyen

doi:10.3934/Neuroscience.2021030

AIMS Neuroscience

2021, Volume 8, Issue 4: 548-557. doi: 10.3934/Neuroscience.2021030

Previous Article Next Article

Mini review Topical Sections

Potential molecular link between the β-amyloid precursor protein (APP) and hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme in Lesch-Nyhan disease and cancer

Khue Vu Nguyen ^{1,2
,
,}

Former Institution Attended:
1.
Department of Medicine, Biochemical Genetics and Metabolism, The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California, San Diego, Building CTF, Room C-103, 214 Dickinson Street, San Diego, CA 92103-8467, USA
2.
Department of Pediatrics, University of California, San Diego, School of Medicine, San Diego, La Jolla, CA 92093-0830, USA

Received: 23 June 2021 Accepted: 25 October 2021 Published: 28 October 2021

Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorders of purine metabolic in which the cytoplasmic enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. Despite having been characterized over 60 years ago, however, up to now, there is no satisfactory explanation of how deficits in enzyme HGprt can lead to LND with the development of the persistent and severe self-injurious behavior. Recently, a role for epistasis between the mutated hypoxanthine phosphoribosyltransferase 1 (HPRT1) and the β-amyloid precursor protein (APP) genes affecting the regulation of alternative APP pre-mRNA splicing in LND has been demonstrated. Furthermore, there were also some reported cases of LND developing thrombosis while APP is an important regulator of vein thrombosis and controls coagulation. Otherwise, the surface expression of HGprt enzyme was also observed in several somatic tissue cancers while APP and the APP-like protein-2 (APLP2) are deregulated in cancer cells and linked to increased tumor cell proliferation, migration, and invasion. The present review provides a discussion about these findings and suggests a potential molecular link between APP and HGprt via epistasis between HPRT1 and APP genes affecting the regulation of alternative APP pre-mRNA splicing. As a perspective, expression vectors for HGprt enzyme and APP are constructed as described in Ref. # 24 (Nguyen KV, Naviaux RK, Nyhan WL (2020) Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). Nucleosides Nucleotides Nucleic Acids 39: 905–922), and they could be used as tools for clarification of these issues. In addition, these expression vectors, especially the one with the glycosyl-phosphatidylinositol (GPI) anchor can be used as a model for the construction of expression vectors for any protein targeting to the cell plasma membrane for studying intermolecular interactions and could be therefore useful in the vaccines as well as antiviral drugs development (studying intermolecular interactions between the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as well as its variants and the angiotensin-converting enzyme 2, ACE2, in coronavirus disease 2019 (COVID-19) [43],[44], for example).
- β-amyloid precursor protein (APP),
- hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme,
- APP gene,
- hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene,
- epistasis,
- epigenetics,
- alternative splicing,
- Lesch-Nyhan disease,
- COVID-19,
- thrombosis,
- cancer,
- antisense drugs
Citation: Khue Vu Nguyen. Potential molecular link between the β-amyloid precursor protein (APP) and hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme in Lesch-Nyhan disease and cancer[J]. AIMS Neuroscience, 2021, 8(4): 548-557. doi: 10.3934/Neuroscience.2021030

Related Papers:

Abstract

Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorders of purine metabolic in which the cytoplasmic enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. Despite having been characterized over 60 years ago, however, up to now, there is no satisfactory explanation of how deficits in enzyme HGprt can lead to LND with the development of the persistent and severe self-injurious behavior. Recently, a role for epistasis between the mutated hypoxanthine phosphoribosyltransferase 1 (HPRT1) and the β-amyloid precursor protein (APP) genes affecting the regulation of alternative APP pre-mRNA splicing in LND has been demonstrated. Furthermore, there were also some reported cases of LND developing thrombosis while APP is an important regulator of vein thrombosis and controls coagulation. Otherwise, the surface expression of HGprt enzyme was also observed in several somatic tissue cancers while APP and the APP-like protein-2 (APLP2) are deregulated in cancer cells and linked to increased tumor cell proliferation, migration, and invasion. The present review provides a discussion about these findings and suggests a potential molecular link between APP and HGprt via epistasis between HPRT1 and APP genes affecting the regulation of alternative APP pre-mRNA splicing. As a perspective, expression vectors for HGprt enzyme and APP are constructed as described in Ref. # 24 (Nguyen KV, Naviaux RK, Nyhan WL (2020) Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). Nucleosides Nucleotides Nucleic Acids 39: 905–922), and they could be used as tools for clarification of these issues. In addition, these expression vectors, especially the one with the glycosyl-phosphatidylinositol (GPI) anchor can be used as a model for the construction of expression vectors for any protein targeting to the cell plasma membrane for studying intermolecular interactions and could be therefore useful in the vaccines as well as antiviral drugs development (studying intermolecular interactions between the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as well as its variants and the angiotensin-converting enzyme 2, ACE2, in coronavirus disease 2019 (COVID-19) [43],[44], for example).

Conflict of interest

The author declares that there are no conflicts of interest.

References

[1]	Stout JT, Caskey CT (1985) HPRT: gene structure, expression, and mutation. Ann Rev Genet 19: 127-148. doi: 10.1146/annurev.ge.19.120185.001015
[2]	Patel PI, Framson PE, Caskey CT, et al. (1986) Fine structure of the human hypoxanthine phosphoribosyl transferase gene. Mol Cell Biol 6: 396-403.
[3]	Lesch M, Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36: 561-570. doi: 10.1016/0002-9343(64)90104-4
[4]	Seegmiller JE, Rosenbloom FM, Kelley WN (1967) Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155: 1682-1684. doi: 10.1126/science.155.3770.1682
[5]	Morton NE, Lalouel JM (1977) Genetic epidemiology of Lesch-Nyhan disease. Am J Hum Genet 29: 304-311.
[6]	Fu R, Ceballos-Picot I, Torres RJ, et al. (2014) For the Lesch-Nyhan disease international study group. Genotype-phenotype correlation in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 137: 1282-1303. doi: 10.1093/brain/awt202
[7]	Micheli V, Bertelli M, Jacomelli G, et al. (2018) Lesch-Nyhan disease: a rare disorder with many unresolved aspects. Medical University 1: 13-24. doi: 10.2478/medu-2018-0002
[8]	Nguyen KV (2014) Epigenetic regulation in amyloid precursor protein and the Lesch-Nyhan syndrome. Biochem Biophys Res Commun 446: 1091-1095. doi: 10.1016/j.bbrc.2014.03.062
[9]	Nguyen KV (2015) Epigenetic regulation in amyloid precursor protein with genomic rearrangements and the Lesch-Nyhan syndrome. Nucleosides Nucleotides Nucleic Acids 34: 674-690. doi: 10.1080/15257770.2015.1071844
[10]	Nguyen KV, Nyhan WL (2017) Quantification of various APP-mRNA isoforms and epistasis in Lesch-Nyhan disease. Neurosci Lett 643: 52-58. doi: 10.1016/j.neulet.2017.02.016
[11]	Imamura A, Yamanouchi H, Kurokawa T (1992) Elevated fibrinopeptide A (FPA) in patients with Lech-Nyhan syndrome. Brain Dev 14: 424-425. doi: 10.1016/S0387-7604(12)80355-X
[12]	Riaz IB, Husnain M, Ateeli H (2014) Recurrent thrombosis in a patient with Lesch-Nyhan syndrome. Am J Med 127: e11-e12. doi: 10.1016/j.amjmed.2014.01.033
[13]	Tewari N, Mathur VP, Sardana D, et al. (2017) Lesch-Nyhan syndrome: the saga of metabolic abnormality and self-injurious behavior. Intractable Rare Dis Res 6: 65-68. doi: 10.5582/irdr.2016.01076
[14]	Canobbio I, Visconte C, Momi S, et al. (2017) Platelet amyloid precursor protein is a modulator of venous thromboembolism in mice. Blood 130: 527-536. doi: 10.1182/blood-2017-01-764910
[15]	Townsend MH, Anderson MD, Weagel EG, et al. (2017) Non-small-cell lung cancer cell lines A549 and NCI-H460 express hypoxanthine guanine phosphoribosyltransferase on the plasma membrane. Onco Targets Ther 10: 1921-1932. doi: 10.2147/OTT.S128416
[16]	Weagel EG, Townsend MH, Anderson MD, et al. (2017) Abstract 2149: Unusual expression of HPRT on the surface of the colorectal cancer cell lines HT29 and SW620. Cancer Res 77: 2149. American Association for Cancer Research Cited 22 May 2018. Available from: (http://cancerres.aacrjournals.org/lookup/doi/10.1158/1538-7445.AM2017-2149).
[17]	Townsend MH, Felsted AM, Ence ZE, et al. (2017) Elevated expression of hypoxanthine guanine phosphoribosyltransferase within malignant tissue. Cancer Clin Oncol 6: 19. doi: 10.5539/cco.v6n2p19
[18]	Townsend MH, Felsted AM, Burrup W, et al. (2018) Examination of hypoxanthine guanine phosphoribosyltransferase as a biomarker for colorectal cancer patients. Mol Cell Oncol 5: e1481810. doi: 10.1080/23723556.2018.1481810
[19]	Townsend MH, Robison RA, O'Neill KL (2018) A review of HPRT and its emerging role in cancer. Med Oncol 35: 89(https://doi.org/10.1007/s12032-018-1144-1). doi: 10.1007/s12032-018-1144-1
[20]	Townsend MH, Shrestha G, Robison RA, et al. (2018) The expansion of targetable biomarkers for CAR T cell therapy. J Exp Clin Cancer Res 37: 163. doi: 10.1186/s13046-018-0817-0
[21]	Townsend MH, Ence ZE, Felsted AM, et al. (2019) Potential new biomarkers for endometrial cancer. Cancer Cell Int 19: 19. doi: 10.1186/s12935-019-0731-3
[22]	Pandey P, Sliker B, Peters HL, et al. (2016) Amyloid precursor protein and amyloid precursor-like protein 2 in cancer. Oncotarget 7: 19430-19444. doi: 10.18632/oncotarget.7103
[23]	Nguyen KV (2019) β-Amyloid precursor protein (APP) and the human diseases. AIMS Neurosci 6: 273-281. doi: 10.3934/Neuroscience.2019.4.273
[24]	Nguyen KV, Naviaux RK, Nyhan WL (2020) Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). Nucleosides Nucleotides Nucleic Acids 39: 905-922. doi: 10.1080/15257770.2020.1714653
[25]	Gottle M, Prudente CN, Fu R, et al. (2014) Loss of dopamine phenotype among midbrain neurone in Lesch-Nyhan disease. Ann Neurol 76: 95-107. doi: 10.1002/ana.24191
[26]	Ceballos-Picot I, Mockel L, Potier MC, et al. (2009) Hypoxanthine-guanine phosphoribosyltransferase regulates early development programming of dopamine neurons: implication for Lesch-Nyhan disease pathogenesis. Hum Mol Genet 18: 2317-2327. doi: 10.1093/hmg/ddp164
[27]	Connolly GP, Duley JA, Stacey NC (2001) Abnormal development of hypoxanthine-guanine phosphoribosyltransferase-deficient CNS neuroblastoma. Brain Res 918: 20-27. doi: 10.1016/S0006-8993(01)02909-2
[28]	Stacey NC, Ma MHY, Duley JA, et al. (2000) Abnormalities in cellular adhesion of neuroblastoma and fibroblast models of Lesch-Nyhan syndrome. Neuroscience 98: 397-401. doi: 10.1016/S0306-4522(00)00149-4
[29]	Harris JC, Lee RR, Jinnah HA, et al. (1998) Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome. Arch Neurol 55: 547-553. doi: 10.1001/archneur.55.4.547
[30]	Schretlen DJ, Varvaris M, Ho TE, et al. (2013) Regional brain volume abnormalities in Lesch-Nyhan disease and its variants: a cross-sectional study. Lancet Neurol 12: 1151-1158. doi: 10.1016/S1474-4422(13)70238-2
[31]	Schretlen DJ, Varvaris M, Tracy D, et al. (2015) Brain white matter volume abnormalities in Lesch-Nyhan disease and its variants. Neurology 84: 190-196. doi: 10.1212/WNL.0000000000001128
[32]	Kang TH, Friedmann T (2015) Alzheimer's disease shares gene expression aberrations with purinergic dysregulation of HPRT deficiency (Lesch-Nyhan disease). Neurosci Lett 590: 35-39. doi: 10.1016/j.neulet.2015.01.042
[33]	Tuner PR, O'Connor K, Tate WP, et al. (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70: 1-32. doi: 10.1016/S0301-0082(03)00089-3
[34]	Zheng H, Koo EH (2006) The amyloid precursor protein: beyond amyloid. Mol Neurodegener 1: 5. doi: 10.1186/1750-1326-1-5
[35]	Nguyen KV (2015) The human β-amyloid precursor protein: biomolecular and epigenetic aspects. Bio Mol Concepts 6: 11-32. doi: 10.1515/bmc-2014-0041
[36]	Xu F, Previti ML, Nieman MT, et al. (2009) AβPP/APLP2 family of Kunitz serine proteinase inhibitors regulate cerebral thrombosis. J Neurosci 29: 5666-5670. doi: 10.1523/JNEUROSCI.0095-09.2009
[37]	Xu F, Davis J, Hoos M, et al. (2017) Mutation of the Kunitz-type proteinase inhibitor domain in the amyloid β-protein precursor abolishes its anti-thrombotic properties in vivo. Thromb Res 155: 58-64. doi: 10.1016/j.thromres.2017.05.003
[38]	Di Luca M, Colciaghi F, Pastorino L, et al. (2000) Platelets as a peripheral district where to study pathogenetic mechanisms of Alzheimer disease: the case of amyloid precursor protein. Eur J Pharmacol 405: 277-283. doi: 10.1016/S0014-2999(00)00559-8
[39]	Cordell HJ (2002) Epistasis: what it means, what it doesn't mean, and statistical method to detect it in humans. Hum Mol Genet 11: 2463-2468. doi: 10.1093/hmg/11.20.2463
[40]	Moore JH (2003) The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 56: 73-82. doi: 10.1159/000073735
[41]	Riordan JD, Nadeau JH (2017) From peas to disease: modifier genes, network resilience, and the genetics of health. Am J Hum Genet 101: 177-191. doi: 10.1016/j.ajhg.2017.06.004
[42]	Saonere JA (2011) Antisense therapy, a magic bullet for the treatment of various diseases: present and future prospects. J Med Genet Genom 3: 77-83.
[43]	Coutard B, Valle C, de Lamballerie X, et al. (2020) The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site in CoV of the same clade. Antiviral Res 176: 104742. doi: 10.1016/j.antiviral.2020.104742
[44]	Nguyen KV (2021) Problems associated with antiviral drugs and vaccines development for COVID-19: approach to intervention using expression vectors via GPI anchor. Nucleosides Nucleotide Nucleic Acids 40: 665-706. doi: 10.1080/15257770.2021.1914851

Reader Comments

Your name:*

Email:*
© 2021 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)