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Changes in the ubiquitination system in children with cerebral palsy

Year 2023, Volume: 13 Issue: 4, 652 - 656, 31.07.2023
https://doi.org/10.16899/jcm.1296330

Abstract

Objective: We aimed to investigate the levels of Ubiquitin Carboxy Terminal Hydrolase-L1 enzyme (UHC-L1), Transactive Response DNA Binding Protein-43 (TDP-43) and Cullin-3 in peripheral blood associated with ubiquitination processes in children with cerebral palsy (CP).
Materials and Methods: We included 50 children with CP in the first patient group. In the control group, there were 30 healthy children who were matched with the patient groups in terms of age and gender. We also recorded risk factors for CP, CP type, botox application, orthosis use, maternal age at birth, and additional problems. Patients aged 6-10 years, diagnosed with CP, without genetic, metabolic disease or mental retardation history were included in this study.
Results: There were 32 female and 18 male patients in the CP group, while there were 19 female and 11 male volunteers in the control group. Maternal age was significantly higher in the CP group (p=0.002). In our study, as a result of the comparison between the control group and the CP group in terms of UCH-L1, TDP-43 and Cullin 3 levels; the levels of UCH-L1 (p=0.048), TDP-43 (p=0.028) and Cullin 3 (p=0.042) in the CP group were found to be statistically significantly lower than the levels of the control group.
Conclusion: The low serum concentrations of UCHL-L1, Cullin 3 and TDP-43 molecules in the CP group and the statistically positive correlation of these molecules with each other may help to understand the neuronal pathophysiology after disruption of the ubiquitination system.

Thanks

Dear Editor, We are sending you our article titled “Changes in the Ubiquitination System in Children with Cerebral Palsy’’ to evaluate its publication in your journal. Disclosure: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We confirm that the data presented in this paper has not been published before, nor has been submitted for publication to another journal or being considered for publication elsewhere. Sincerely,

References

  • 1. Inoue T, Shiraki K, Fuke H, et al. Proteasome inhibition sensitizes heptocelluler carcinoma cells to trail by suppressing caspase inhibitors and AKT patway. Anticancer Drugs 2006;17(3):261-268.
  • 2. Sánchez-Sánchez J, Arévalo JC. A review on ubiquitination of neurotrophin receptors: Facts and perspectives. Int J Mol Sci 2017;18:630.
  • 3. Yau R, Rape M. The increasing complexity of the ubiquitin code. Nat Cell Biol 2016;18:579–586.
  • 4. Martinez-Vicente M, Sovak G, Cuervo AM. Protein degradation and aging. Exp Gerontol 2005;40(8-9):622-33.
  • 5. Zheng Q, Huang T, Zhang L, et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front Aging Neurosci 2016;8:303.
  • 6. Dawson SP. Hepatocellular carcinoma and the ubiquitin-proteasome system, Biochim Biophys Acta 2008;1782(12)77:5-84.
  • 7. Gulati S, Sondhi V. Cerebral palsy: an overview. Indian J Pediatr 2018;85:1006-1016.
  • 8. Paul S, Nahar A, Bhagawati M, Kunwar AJ. A Review on Recent Advances of Cerebral Palsy. Oxid Med Cell Longev 2022:2622310
  • 9. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006;443(7113):787-795.
  • 10. Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules 2019;24(8):1583.
  • 11. Marret S, Vanhulle C, Laquerriere A. Pathophysiology of cerebral palsy. In Pediatric Neurology Part I; Elsevier: Amsterdam, The Netherlands 2013;111;169–176.
  • 12. Aycicek A, Iscan A. Oxidative and antioxidative capacity in children with cerebral palsy. Brain res bul 2006;69(6):666-668.
  • 13. Lee SY, Ramirez J, Franco M, et al. Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10. Cell Mol Life 2014;71(14):2747-58.
  • 14. Setsuie R, Wada K. The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem Int 2007;51:105-111.
  • 15. Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med 2014;20:1242–1253.
  • 16. Diaz-Arrastia R, Wang KK, Papa L, Sorani MD, Yue JK, Puccio AM. Acute biomarkers of traumatic brain injury: relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. J Neurotrauma 2014;31(1):19-25.
  • 17. Dong L, Chang Q, Ma J, et al. Associations of blood UCH-L1 and NfL levels with cognitive dysfunction in Parkinson’s disease patients. Neuroscience Letters 2023;804:137219.
  • 18. Blyth BJ, Farahvar A, He H, et al. Elevated serum ubiquitin carboxy-terminal hydrolase L1 is associated with abnormal blood-brain barrier function after traumatic brain injury. J neurotrauma 2011;28(12):2453-62.
  • 19. Ren C, Kobeissy F, Alawieh A, Li N, Zibara K, Mondello S. Assessment of serum UCH-L1 and GFAP in acute stroke patients. Sci rep 2016;6(1):1-9.
  • 20. Brophy GM, Mondello S, Papa L, et al. Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids. J neurotrauma 2011;28(6):861-870.
  • 21. Papa L, Lewis L M, Silvestri S, et al. Serum levels of Ubiquitin C-terminal Hydrolase (UCH-L1) distinguish mild traumatic brain injury (TBI) from trauma controls and are elevated in mild and moderate TBI patients with intracranial lesions and neurosurgical intervention. J Trauma Acute Care Surg 2012;72(5):1335.
  • 22. Lewis SB, Wolper R, Chi YY, et al. Identification and preliminary characterization of ubiquitin C terminal hydrolase 1 UCHL1 as a biomarker of neuronal loss in aneurysmal subarachnoid hemorrhage. J Neurosci Res 2010;88: 1475-1484.
  • 23. Douglas-Escobar M, Yang C, Bennett J, et al. A pilot study of novel biomarkers in neonates with hypoxic-ischemic encephalopathy. Pediatr Res 2010;68:531-536
  • 24. Mondello S, Palmio J, Streeter J, Hayes RL, Peltola J, Jeromin A. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC neurol 2012;12(1), 1-7.
  • 25. Li Y, Wang Z, Zhang B, et al. Cerebrospinal fluid ubiquitin C-terminal hydrolase as a novel marker of neuronal damage after epileptic seizure. Epilepsy Res 2013;103:205-10.
  • 26. Xu JB, Tong GL. Efficacy and mechanism of scalp acupuncture for spastic cerebral palsy. Zhongguo Zhen Jiu 2023;43(2):163-169.
  • 27. Stover CM, Lynch NJ, Hanson SJ, Windbichler M, Gregory SG, Schwaeble WJ. Organization of the MASP2 locus and its expression profile in mouse and rat. Mamm Genome 2004;15:887–900.
  • 28. De Conti L, Akinyi MV, Mendoza-Maldonado R, Romano M, Baralle M, Buratti E. TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways. Nucleic Acids Res 2015;43:8990–9005.
  • 29. Feneberg E, Gray E, Ansorge O, Talbot K, Turner MR. Towards a TDP-43-Based Biomarker for ALS and FTLD. Mol Neurobiol 2018;55:7789–7801.
  • 30. Meneses A, Koga S, O’Leary J, Dickson DW, Bu G, Zhao N. TDP-43 pathology in Alzheimer’s disease. Mol neurodegener 2021;16:1-15.
  • 31. Uchino A, Takao M, Hatsuta H, Sumikura H, Nakano Y, Nogami A, et al. Incidence and extent of TDP-43 accumulation in aging human brain. Acta Neuropathol Commun 2015;3:35.
  • 32. Nag S, Yu L, Boyle PA, Leurgans SE, Bennett DA, Schneider JA. TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer's disease. Acta Neuropathol Commun 2018;6:33
  • 33. Geser F, Winton MJ, Kwong LK, et al. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 2008;115(1):133–145.
  • 34. Sarikas A, Hartmann T, Pan ZQ. The cullin protein family. Genome biol 2011;12:1-12.
  • 35. Andérica-Romero AC, González-Herrera IG, Santamaría A, Pedraza-Chaverri J. Cullin 3 as a novel target in diverse pathologies. Redox biol 2013;1(1):366-372.

Serebral palsili çocuklarda ubiqinitasyon sistemindeki değişiklikler

Year 2023, Volume: 13 Issue: 4, 652 - 656, 31.07.2023
https://doi.org/10.16899/jcm.1296330

Abstract

Amaç: Serebral palsili (SP) çocuklarda ubikitinasyon süreçleri ile ilişkili periferik kanda Ubiquitin Karboksi Terminal Hidrolaz-L1 enzimi (UHC-L1), Transaktif Yanıt DNA Bağlayıcı Protein-43 (TDP-43) ve Cullin-3 düzeylerini araştırmayı amaçladık. .
Materyal ve Metod: Birinci grubuna SP'li 50 hasta dahil edildi. Kontrol grubunda yaş ve cinsiyet açısından hasta grupları ile eşleşen 30 sağlıklı çocuk vardı. SP, SP tipi, botoks uygulaması, ortez kullanımı, annenin doğum yaşı ve ek sorunlar için risk faktörlerini kayddildi. Bu çalışmaya 6-10 yaş arası, SP tanısı almış, genetik, metabolik hastalık veya mental retardasyon öyküsü olmayan hastalar dahil edildi.
Bulgular: SP grubunda 32 kadın ve 18 erkek hasta bulunurken, kontrol grubunda 19 kadın ve 11 erkek gönüllü vardı. Anne yaşı SP grubunda anlamlı olarak yüksekti (p=0,002). Çalışmamızda kontrol grubu ile SP grubunun UCH-L1, TDP-43 ve Cullin 3 düzeyleri açısından karşılaştırılması sonucunda; SP grubunda UCH-L1 (p=0,048), TDP-43 (p=0,028) ve Cullin 3 (p=0,042) düzeyleri kontrol grubuna göre istatistiksel olarak anlamlı düşük bulundu.
Sonuç: SP grubundaki UCHL-L1, Cullin 3 ve TDP-43 moleküllerinin düşük serum konsantrasyonları ve bu moleküllerin birbirleriyle istatistiksel olarak pozitif korelasyonu, ubiquitination sisteminin bozulmasından sonra nöronal patofizyolojinin anlaşılmasına yardımcı olabilir.

References

  • 1. Inoue T, Shiraki K, Fuke H, et al. Proteasome inhibition sensitizes heptocelluler carcinoma cells to trail by suppressing caspase inhibitors and AKT patway. Anticancer Drugs 2006;17(3):261-268.
  • 2. Sánchez-Sánchez J, Arévalo JC. A review on ubiquitination of neurotrophin receptors: Facts and perspectives. Int J Mol Sci 2017;18:630.
  • 3. Yau R, Rape M. The increasing complexity of the ubiquitin code. Nat Cell Biol 2016;18:579–586.
  • 4. Martinez-Vicente M, Sovak G, Cuervo AM. Protein degradation and aging. Exp Gerontol 2005;40(8-9):622-33.
  • 5. Zheng Q, Huang T, Zhang L, et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front Aging Neurosci 2016;8:303.
  • 6. Dawson SP. Hepatocellular carcinoma and the ubiquitin-proteasome system, Biochim Biophys Acta 2008;1782(12)77:5-84.
  • 7. Gulati S, Sondhi V. Cerebral palsy: an overview. Indian J Pediatr 2018;85:1006-1016.
  • 8. Paul S, Nahar A, Bhagawati M, Kunwar AJ. A Review on Recent Advances of Cerebral Palsy. Oxid Med Cell Longev 2022:2622310
  • 9. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006;443(7113):787-795.
  • 10. Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules 2019;24(8):1583.
  • 11. Marret S, Vanhulle C, Laquerriere A. Pathophysiology of cerebral palsy. In Pediatric Neurology Part I; Elsevier: Amsterdam, The Netherlands 2013;111;169–176.
  • 12. Aycicek A, Iscan A. Oxidative and antioxidative capacity in children with cerebral palsy. Brain res bul 2006;69(6):666-668.
  • 13. Lee SY, Ramirez J, Franco M, et al. Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10. Cell Mol Life 2014;71(14):2747-58.
  • 14. Setsuie R, Wada K. The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem Int 2007;51:105-111.
  • 15. Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med 2014;20:1242–1253.
  • 16. Diaz-Arrastia R, Wang KK, Papa L, Sorani MD, Yue JK, Puccio AM. Acute biomarkers of traumatic brain injury: relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. J Neurotrauma 2014;31(1):19-25.
  • 17. Dong L, Chang Q, Ma J, et al. Associations of blood UCH-L1 and NfL levels with cognitive dysfunction in Parkinson’s disease patients. Neuroscience Letters 2023;804:137219.
  • 18. Blyth BJ, Farahvar A, He H, et al. Elevated serum ubiquitin carboxy-terminal hydrolase L1 is associated with abnormal blood-brain barrier function after traumatic brain injury. J neurotrauma 2011;28(12):2453-62.
  • 19. Ren C, Kobeissy F, Alawieh A, Li N, Zibara K, Mondello S. Assessment of serum UCH-L1 and GFAP in acute stroke patients. Sci rep 2016;6(1):1-9.
  • 20. Brophy GM, Mondello S, Papa L, et al. Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids. J neurotrauma 2011;28(6):861-870.
  • 21. Papa L, Lewis L M, Silvestri S, et al. Serum levels of Ubiquitin C-terminal Hydrolase (UCH-L1) distinguish mild traumatic brain injury (TBI) from trauma controls and are elevated in mild and moderate TBI patients with intracranial lesions and neurosurgical intervention. J Trauma Acute Care Surg 2012;72(5):1335.
  • 22. Lewis SB, Wolper R, Chi YY, et al. Identification and preliminary characterization of ubiquitin C terminal hydrolase 1 UCHL1 as a biomarker of neuronal loss in aneurysmal subarachnoid hemorrhage. J Neurosci Res 2010;88: 1475-1484.
  • 23. Douglas-Escobar M, Yang C, Bennett J, et al. A pilot study of novel biomarkers in neonates with hypoxic-ischemic encephalopathy. Pediatr Res 2010;68:531-536
  • 24. Mondello S, Palmio J, Streeter J, Hayes RL, Peltola J, Jeromin A. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC neurol 2012;12(1), 1-7.
  • 25. Li Y, Wang Z, Zhang B, et al. Cerebrospinal fluid ubiquitin C-terminal hydrolase as a novel marker of neuronal damage after epileptic seizure. Epilepsy Res 2013;103:205-10.
  • 26. Xu JB, Tong GL. Efficacy and mechanism of scalp acupuncture for spastic cerebral palsy. Zhongguo Zhen Jiu 2023;43(2):163-169.
  • 27. Stover CM, Lynch NJ, Hanson SJ, Windbichler M, Gregory SG, Schwaeble WJ. Organization of the MASP2 locus and its expression profile in mouse and rat. Mamm Genome 2004;15:887–900.
  • 28. De Conti L, Akinyi MV, Mendoza-Maldonado R, Romano M, Baralle M, Buratti E. TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways. Nucleic Acids Res 2015;43:8990–9005.
  • 29. Feneberg E, Gray E, Ansorge O, Talbot K, Turner MR. Towards a TDP-43-Based Biomarker for ALS and FTLD. Mol Neurobiol 2018;55:7789–7801.
  • 30. Meneses A, Koga S, O’Leary J, Dickson DW, Bu G, Zhao N. TDP-43 pathology in Alzheimer’s disease. Mol neurodegener 2021;16:1-15.
  • 31. Uchino A, Takao M, Hatsuta H, Sumikura H, Nakano Y, Nogami A, et al. Incidence and extent of TDP-43 accumulation in aging human brain. Acta Neuropathol Commun 2015;3:35.
  • 32. Nag S, Yu L, Boyle PA, Leurgans SE, Bennett DA, Schneider JA. TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer's disease. Acta Neuropathol Commun 2018;6:33
  • 33. Geser F, Winton MJ, Kwong LK, et al. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 2008;115(1):133–145.
  • 34. Sarikas A, Hartmann T, Pan ZQ. The cullin protein family. Genome biol 2011;12:1-12.
  • 35. Andérica-Romero AC, González-Herrera IG, Santamaría A, Pedraza-Chaverri J. Cullin 3 as a novel target in diverse pathologies. Redox biol 2013;1(1):366-372.
There are 35 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Original Research
Authors

Ayşe Gülşen Doğan 0000-0002-2542-4999

İhsan Çetin 0000-0002-0937-0054

Early Pub Date July 25, 2023
Publication Date July 31, 2023
Acceptance Date June 8, 2023
Published in Issue Year 2023 Volume: 13 Issue: 4

Cite

AMA Doğan AG, Çetin İ. Changes in the ubiquitination system in children with cerebral palsy. J Contemp Med. July 2023;13(4):652-656. doi:10.16899/jcm.1296330