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WWOX is a Risk Factor for Alzheimer’s Disease: How and Why?

Chun-I Sze

Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan, Taiwan, ROC

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Kuang-Yu Wen

Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

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, and

Nan-Shan Chang

Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan, ROC

Department of Neurochemistry, New York State Institute for Basic, Research in Developmental Disabilities, Staten Island, NY 10314, USA

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan, ROC

E-mail Address: changns@mail.ncku.edu.a

Correspondence: Nan-Shan Chang, Institute of Molecular Medicine, National Cheng Kung University, Tainan 70101, Taiwan, ROC.

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https://doi.org/10.1142/S2591722620400037Cited by:2 (Source: Crossref)

Abstract

A recent large genome-wide association meta-analysis revealed that the human WWOX gene is regarded as one of the five newly identified risk factors for Alzheimer’s disease (AD). However, this study did not functionally characterize how WWOX protein deficiency affects AD initiation, progression and neurodegeneration. In this review, evidence and perspectives are provided regarding how WWOX works in limiting neurodegeneration. Firstly, loss of WWOX/Wwox gene leads to severe neural diseases with degeneration, metabolic disorder and early death in the newborns. Downregulation of pY33-WWOX may start at middle ages, and this leads to slow aggregation of a cascade of proteins, namely TRAPPC6A $Δ$ , TIAF1 and SH3GLB2, that leads to amyloid-beta (A $β$ ) formation and tau tangle formation in old-aged AD patients. Secondly, functional antagonism between tumor suppressors p53 and WWOX may occur in vivo, in which p53-mediated inflammation is blocked by WWOX. Loss of balance in the functional antagonism leads to aggregation of pathogenic proteins for AD such as tau and A $β$ in the brain cortex and hippocampus. Thirdly, downregulation of pY33-WWOX is accompanied by upregulation of pS14-WWOX. The event frequently correlates with enhanced AD progression and cancer cell growth in vivo. A small peptide Zfra4-10 dramatically suppresses pS14-WWOX and restores memory loss in triple transgenic (3xTg) mice, and inhibits cancer growth in mice as well. Finally, a supporting scenario is that WWOX deficiency induces enhanced cell migration and loss of cell-to-cell recognition. This allows the generation of neuronal heterotopia and associated epileptic seizure in WWOX-deficient newborn patients.

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References

1. Y. A. Chen, C. Y. Lu, T. Y. Cheng, S. H. Pan, H. F. Chen and N. S. Chang, WW domain-containing proteins YAP and TAZ in the hippo pathway as key regulators in stemness maintenance, tissue homeostasis, and tumorigenesis, Front. Oncol. 9 (2019) 60. Crossref, Google Scholar
2. S. S. Huang, L. J. Hsu and N. S. Chang, Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system. FASEB Bioadv. 2(4) (2020) 234–253. Crossref, Google Scholar
3. C. C. Liu et al., WWOX Phosphorylation, Signaling, and Role in Neurodegeneration, Front. Neurosci. 12 (2018) 563. Crossref, Google Scholar
4. N. S. Chang, L. J. Hsu, Y. S. Lin, F. J. Lai and H. M. Sheu, WW domain-containing oxidoreductase: A candidate tumor suppressor, Trends Mol. Med. 13(1) (2007) 12–22. Crossref, Google Scholar
5. M. Abu-Odeh, T. Bar-Mag, H. Huang, T. Kim, Z. Salah, S. K. Abdeen, M. Sudol, D. Reichmann, S. Sidhu, P. M. Kim and R. I. Aqeilan, Characterizing WW domain interactions of tumor suppressor WWOX reveals its association with multiprotein networks, J. Biol. Chem. 289(13) (2014) 8865–8880. Crossref, Google Scholar
6. S. K. Abdeen, U. Ben-David, A. Shweiki, B. Maly and R. I. Aqeilan, Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer. Cell Death Dis. 9(8) (2018) 832. Crossref, Google Scholar
7. N. S. Chang, J. Doherty, A. Ensign, L. Schultz, L. J. Hsu and Q. Hong, WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53. J. Biol. Chem. 280(52) (2005) 43100–43108. Crossref, Google Scholar
8. S. J. Chen, P. W. Lin, H. P. Lin, S. S. Huang, F. J. Lai, H. M. Sheu, L. J. Hsu and N. S. Chang, UV irradiation/cold shock-mediated apoptosis is switched to bubbling cell death at low temperatures. Oncotarget 6(10) (2015) 8007–8018. Crossref, Google Scholar
9. N. S. Chang, Bubbling cell death: A hot air balloon released from the nucleus in the cold, Exp. Biol. Med. (Maywood). 241(12) (2016) 1306–1315. Crossref, Google Scholar
10. L. J. Hsu et al., Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed, Oncotarget 8(12) (2017) 19137. Crossref, Google Scholar
11. L. J. Hsu et al., Transforming growth factor $β$ 1 signaling via interaction with cell surface Hyal-2 and recruitment of WWOX/WOX1, J. Biol. Chem. 284(23) (2009) 16049–16059. Crossref, Google Scholar
12. W. J. Wang et al., WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX $_{7 - 21}$ and WWOX $_{7 - 11}$ for Signaling Cancer Growth Suppression and Prevention In Vivo. Cancers (Basel). 11 (2019) 1818. Crossref, Google Scholar
13. W. P. Su et al., Therapeutic Zfra4-10 or WWOX7-21 peptide induces complex formation of WWOX with global protein targets in organs that leads to cancer suppression and spleen cytotoxic memory Z cell activation in vivo, Cancers (Basel). (2020) in press. Crossref, Google Scholar
14. M. H. Lee et al., Zfra activates memory Hyal-2 $+$ CD3 $-$ CD19 $-$ spleen cells to block cancer growth, stemness, and metastasis in vivo, Oncotarget 6(6) (2015) 3737. Crossref, Google Scholar
15. M. H. Lee et al., Zfra restores memory deficits in Alzheimer’s disease triple-transgenic mice by blocking aggregation of TRAPPC6A $Δ$ , SH3GLB2, tau, and amyloid $β$ , and inflammatory NF- $κ$ B activation, Alzheimers Dement. (N Y). 3(2) (2017) 189–204. Crossref, Google Scholar
16. P. Y. Chou et al., Strategies by which WWOX-deficient metastatic cancer cells utilize to survive via dodging, compromising, and causing damage to WWOX-positive normal microenvironment, Cell Death Discov. 5(97) (2019) 1–13. Google Scholar
17. S. N. Ehaideb, M. J. Al-Bu Ali, J. J. Al-Obaid, K. M. Aljassim and M. Alfadhel, Novel homozygous mutation in the WWOX gene causes seizures and global developmental delay: Report and review, Transl. Neurosci. 9 (2018) 203–208. Crossref, Google Scholar
18. C. M. Aldaz, B. W. Ferguson and M. C. Abba, WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies, Biochim. Biophys. Acta. 1846(1) (2014) 188–200. Google Scholar
19. J. Piard et al., The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature, Genetics in Medicine 21 (2019) 1308. Crossref, Google Scholar
20. L. Elsaadany, M. El-Said, R. Ali, H. Kamel and T. Ben-Omran, W44X mutation in the WWOX gene causes intractable seizures and developmental delay: A case report, BMC Med. Genet. 17(1) (2016) 1–6. Crossref, Google Scholar
21. Y. Y. Cheng et al., Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3 $β$ -mediated epileptic seizure activity in mice, Acta. Neuropathol. Commun. 8(1) (2020) 1–16. Crossref, Google Scholar
22. T. Hussain et al., Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus, Neurobiol. Dis. 121 (2019) 163–176. Crossref, Google Scholar
23. J. Y. Chang and N. S. Chang, WWOX dysfunction induces sequential aggregation of TRAPPC6A $Δ$ , TIAF1, tau and amyloid $β$ , and causes apoptosis, Cell Death Discov. 1 (2015) 1–11. Crossref, Google Scholar
24. B. W. Kunkle et al., Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates A $β$ , tau, immunity and lipid processing, Nature Genet. 51(3) (2019) 414–430. Crossref, Google Scholar
25. S. T. Chen, J. L. Chuang, J. P. Wang, M. S. Tsai, H. Li and N. S. Chang, Expression of WW domain-containing oxidoreductase WOX1 in the developing murine nervous system, Neuroscience 124(4) (2004) 831–839. Crossref, Google Scholar
26. T. Si, G. Xing and Y. Han, Subjective Cognitive Decline and Related Cognitive Deficits, Front. Neurol. 11 (2020) 247. Crossref, Google Scholar
27. T. B. Van Itallie, Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE), Metabolism 100S (2019) 153943. Crossref, Google Scholar
28. H. Cho, S. J. Hyeon, J. Y. Shin, V. E. Alvarez, T. D. Stein, J. Lee, N. W. Kowall, A. C. McKee, H. Ryu and J. S. Seo, Alterations of transcriptome signatures in head trauma-related neurodegenerative disorders, Sci. Rep. 10(1) (2020) 8811. Crossref, Google Scholar
29. S. Hosomi, M. Ohnishi, H. Ogura and T. Shimazu, Traumatic brain injury-related inflammatory projection: Beyond local inflammatory responses, Acute Med. Surg. 7 (2020) e520. Crossref, Google Scholar
30. V. Dinet, K. G. Petry and J. Badaut, Brain-immune interactions and neuroinflammation after traumatic brain injury, Front. Neurosci. 13 (2019) 1178. Crossref, Google Scholar
31. M. Chen, S. R. Edwards and D. C. Reutens, Complement in the Development of Post-Traumatic Epilepsy: Prospects for Drug Repurposing, J. Neurotrauma. 37(5) (2020) 692–705. Crossref, Google Scholar
32. L. J. Hsu et al., Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed, Oncotarget 8(12) (2017) 19137. Crossref, Google Scholar
33. W. P. Su, W. J. Wang, C. I. Sze and N. S. Chang, Zfra Induction of Memory Anticancer Response via a Novel Immune Cell, Oncoimmunology, 5(9) (2016) e1213935. Crossref, Google Scholar
34. L. J. Hsu et al., HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response, Front. Cell Dev. Biol. 4 (2016) 141. Crossref, Google Scholar
35. C. I. Sze et al., A cascade of protein aggregation bombards mitochondria for neurodegeneration and apoptosis under WWOX deficiency, Cell Death Dis. 6(9) (2015) e1881. Crossref, Google Scholar
36. J. Y. Chang et al., Trafficking protein particle complex 6A delta (TRAPPC6A $Δ)$ is an extracellular plaque-forming protein in the brain, Oncotarget 6(6) (2015) 3578. Crossref, Google Scholar
37. M. H. Lee et al., TGF- $β$ induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid $β$ plaques in Alzheimer’s disease, Cell Death Dis. 1(12) (2010) e110–e110. Crossref, Google Scholar
38. C. I. Sze et al., Down-regulation of WW domain-containing oxidoreductase induces tau phosphorylation in vitro a potential role in ALZHEIMER’S disease, J. Biol. Chem. 279(29) (2004) 30498–30506. Crossref, Google Scholar
39. H. Y. Wang et al., WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3 $β$ , Cell Death Differ. 19(6) (2012) 1049–1059. Crossref, Google Scholar
40. S. T. Chen, J. I. Chuang, C. L. Cheng, L. J. Hsu and N. S. Chang, Light-induced retinal damage involves tyrosine 33 phosphorylation, mitochondrial and nuclear translocation of WW domain-containing oxidoreductase in vivo, Neuroscience 130(2) (2005) 397–407. Crossref, Google Scholar
41. M. Y. Li et al., Dramatic co-activation of WWOX/WOX1 with CREB and NF- $κ$ B in delayed loss of small dorsal root ganglion neurons upon sciatic nerve transection in rats, PLoS One 4(11) (2009) e7820. Crossref, Google Scholar
42. S. Dudekula, M. H. Lee, L. J. Hsu, S. J. Chen and N. S. Chang, Zfra is a small wizard in the mitochondrial apoptosis, Aging (Albany NY) 2(12) (2010) 1023. Crossref, Google Scholar
43. L. J. Hsu, Q. Hong, L. Schultz, E. Kuo, M. H. Lee, Y. S. Lin and N. S. Chang, Zfra is an inhibitor of Bcl-2 expression and cytochrome c release from the mitochondria, Cell Signal. 20(7) (2008) 1303–1312. Crossref, Google Scholar
44. M. S. Schrock et al., WWOX–Brca1 interaction: Role in DNA repair pathway choice, Oncogene 36(16) (2017) 2215–2227. Crossref, Google Scholar
45. M. Abu-Odeh, N. A. Hereema and R. I. Aqeilan, WWOX modulates the ATR-mediated DNA damage checkpoint response, Oncotarget 7(4) (2016) 4344. Crossref, Google Scholar
46. Q. Hong, L. J. Hsu, L. Schultz, N. Pratt, J. Mattison and N. S. Chang, Zfra affects TNF-mediated cell death by interacting with death domain protein TRADD and negatively regulates the activation of NF- $κ$ B, JNK1, p53 and WOX1 during stress response, BMC Mol. Biol. 8 (2007) 50. Crossref, Google Scholar
47. H. L. Kuo, P. C. Ho, S. S. Huang and N. S. Chang, Chasing the signaling run by tri-molecular time-lapse FRET microscopy, Cell Death Discov. 4(45) (2018) 1–9. Google Scholar
48. S. J. Chen et al., UV irradiation/cold shock-mediated apoptosis is switched to bubbling cell death at low temperatures, Oncotarget 6(10) (2015) 8007. Crossref, Google Scholar
49. M. Sacher, N. Shahrzad, H. Kamel and M. P. Milev, TRAPPopathies: An emerging set of disorders linked to variations in the genes encoding transport protein particle (TRAPP)-associated proteins, Traffic 20(1) (2019) 5–26. Crossref, Google Scholar
50. N. S. Chang, J. Doherty, A. Ensign, L. Schultz, L. J. Hsu and Q. Hong, WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53, J. Biol. Chem. 280(52) (2005) 43100–43108. Crossref, Google Scholar
51. N. S. Chang, J. Doherty and A. Ensign, JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis, J. Biol. Chem. 278(11) (2003) 9195–9202. Crossref, Google Scholar
52. N. S. Chang et al., Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity, J. Biol. Chem. 276(5) (2001) 3361–3370. Crossref, Google Scholar
53. P. Y. Chou, S. R. Lin, M. H. Lee, L. Schultz, C. I. Sze and N. S. Chang, A p53/TIAF1/WWOX triad exerts cancer suppression but may cause brain protein aggregation due to p53/WWOX functional antagonism, Cell Commun. and Signal. 17(1) (2019) 1–16. Crossref, Google Scholar
54. L. Schultz, S. Khera, D. Sleve, J. Heath and N. S. Chang, TIAF1 and p53 functionally interact in mediating apoptosis and silencing of TIAF1 abolishes nuclear translocation of serine 15-phosphorylated p53, DNA Cell Biol. 23(1) (2004) 67–74. Crossref, Google Scholar
55. J. Y. Chang et al., TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death, Cell Death Dis. 3(4) (2012) e302–e302. Crossref, Google Scholar
56. Q. Hong et al., Self-aggregating TIAF1 in lung cancer progression, Transl. Respir. Med. 1(1) (2013) 5. Crossref, Google Scholar
57. S. S. Huang, W. P. Su, H. P. Lin, H. L. Kuo, H. L. Wei and N. S. Chang, Role of WW domain-containing oxidoreductase WWOX in driving T cell acute lymphoblastic leukemia maturation, J. Biol. Chem. 291(33) (2016) 17319–17331. Crossref, Google Scholar
58. S. S. Huang and N. S. Chang, Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events, Exp. Biol. Med. (Maywood). 243(2) (2018) 137–147. Crossref, Google Scholar
59. Y. Chang, Y. Y. Lan, J. R. Hsiao and N. S. Chang, Strategies of oncogenic microbes to deal with WW domain-containing oxidoreductase, Exp. Biol. Med. (Maywood). 240(3) (2015) 329–337. Crossref, Google Scholar
60. J. Fu, Z. Qu, P. Yan, C. Ishikawa, R. I. Aqeilan, A. B. Rabson and G. Xiao, The tumor suppressor gene WWOX links the canonical and noncanonical NF- $κ$ B pathways in HTLV-I Tax-mediated tumorigenesis, Blood 117(5) (2011) 1652–1661. Crossref, Google Scholar
61. J. Yan, M. Zhang, J. Zhang, X. Chen and X. Zhang, Helicobacter pylori infection promotes methylation of WWOX gene in human gastric cancer, Biochem. Biophys. Res. Commun. 408(1) (2011) 99–102. Crossref, Google Scholar
62. Q. Shaukat, J. Hertecant, A. W. El-Hattab, B. R. Ali and J. Suleiman, West syndrome, developmental and epileptic encephalopathy, and severe CNS disorder associated with WWOX mutations, Epileptic Disord. 20(5) (2018) 401–412. Crossref, Google Scholar
63. J. Johannsen et al., A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay, Neurogenetics 19(3) (2018) 151–156. Crossref, Google Scholar
64. B. Tabarki, A. AlHashem, S. AlShahwan, F. S. Alkuraya, S. Gedela and G. Zuccoli, Severe CNS involvement in WWOX mutations: Description of five new cases, Am. J. Med. Genet. A. 167A(12) (2015) 3209–3213. Crossref, Google Scholar
65. C. Mignot et al., WWOX-related encephalopathies: Delineation of the phenotypical spectrum and emerging genotype-phenotype correlation, J. Med. Genet. 52(1) (2015) 61–70. Crossref, Google Scholar
66. J. He, W. Zhou, J. Shi, B. Zhang and H. Wang, A Chinese patient with epilepsy and WWOX compound heterozygous mutations, Epileptic Disord. 22(1) (2020) 120–124. Google Scholar
67. S. Schiller, H. Rosewich, S. Grünewald and J. Gärtner, Inborn errors of metabolism leading to neuronal migration defects, J. Inherit Metab. Dis. 43(1) (2020) 145–155. Crossref, Google Scholar
68. N. C. Armstrong, R. C. Anderson and K. W. McDermott, Reelin: Diverse roles in central nervous system development, health and disease, Int. J. Biochem. Cell Biol. 112 (2019) 72–75. Crossref, Google Scholar
69. B. Roberts, Neuronal migration disorders, Radiol. Technol. 89(3) (2018) 279–295. Google Scholar
70. D. M. Romero, N. Bahi-Buisson and F. Francis, Genetics and mechanisms leading to human cortical malformations, Semin Cell Dev. Biol. 76 (2018) 33–75. Crossref, Google Scholar
71. A. A. Ayanlaja et al., Distinct features of Doublecortin as a marker of neuronal migration and its implications in Cancer cell mobility, Front. Mol. Neurosci. 10 (2017) 199. Crossref, Google Scholar
72. C. P. Lo et al., MPP $+$ -induced neuronal death in rats involves tyrosine 33 phosphorylation of WW domain-containing oxidoreductase WOX1. Eur J Neurosci. 27 (2008) 1634–1646. Crossref, Google Scholar
73. N. S. Chang, unpublished, forthcoming (2022). Google Scholar