Otizm Spektrum Bozukluğu Olan Hastalarda Öğrenme ve Hafıza Bozukluklarının NEURL1 ve RGS14 Genleri ile İlişkisi

Öz

Amaç: Bu çalışmada OSB hastalarında öğrenme ve hafıza güçlükleri ile NEURL1 ve RGS14 genleri arasındaki ilişkiyi değerlendirmeyi amaçladık.

Yöntem: Bu çalışmaya OSB'li 40 çocuk (20 OSB, 20 yüksek fonksiyonlu otizm (HFA)) ve 20 sağlıklı kontrol dahil edildi. Gönüllülerin kan örneklerinde NEURL1 ve RGS14 genlerinin ekspresyonları kantitatif Real-Time PCR (qRT-PCR) yöntemi ile değerlendirildi. Hastalardaki klinik ve demografik bulgular belirlenerek gen ekspresyonları ile ilişkisi incelendi.

Bulgular: Bulgularımıza göre her iki hasta grubunda da kontrol grubuna göre NEURL1 gen ekspresyonu azaldı (p<0.05). RGS14 geni açısından gruplar arasında anlamlı fark yoktu (p>0.05). HFA hastalarında öğrenme ve bellek güçlükleri ile RGS14 gen ekspresyonu arasında istatistiksel olarak anlamlı bir ilişki bulundu (p = 0.045). OSB hastalarının NEURL1 ve RGS14 gen ekspresyonları arasında pozitif korelasyon görüldü (p=0.032, r=0,59).

Sonuç: Bu çalışmada NEURL1 geninin OSB hastalarında öğrenme ve hafıza güçlüğünü etkileyebileceğini gösterdik. Ancak, her iki genin daha fazla hasta ve tercihen beyin dokuları ile çalışılmasını öneriyoruz. Bu genler ilk kez otizmle ilgili bir klinik çalışmada değerlendirilmiştir, bu açıdan literatüre katkı sağlayacağına inanıyoruz.

Anahtar Kelimeler

• Otizm
• NEURL1
• RGS14
• Öğrenme
• Hafıza

The relationship of learning and memory disfunction with NEURL1 and RGS14 genes in patients with autism spectrum disorders

Öz

Aim: We aimed to evaluate the relationship between learning-memory difficulties and NEURL1 and RGS14 genes in patients with autism spectrum disorders (ASD).

Method: Forty children with ASD (20 ASD, 20 high functioning autism (HFA)) and 20 healthy controls were enrolled in this study. NEURL1 and RGS14 gene expressions in blood samples of volunteers were assessed by quantitative Real-Time PCR (qRT-PCR). The clinical and demographical findings in patients were determined and examined in relation to the gene expressions.

Results: According to our findings, NEURL1 gene expression was decreased in both patient groups compared to the control (p<0.05). No significant difference between the groups in terms of the RGS14 gene (p>0.05). A statistically significant correlation was found between learning and memory difficulties and RGS14 gene expression in HFA patients (p=0.045). A positive correlation was observed between NEURL1 and RGS14 gene expressions of ASD patients (p=0.032, r=0,59).

Conclusion: In this study, we showed that the NEURL1 gene may affect learning and memory difficulties in ASD patients. Nonetheless, we recommend that both genes be studied with more patients and preferably with brain tissues. These genes were evaluated for the first time in a clinical study on autism, and we believe that they will contribute to the literature in this respect. 

Anahtar Kelimeler

• Autism
• Neuralized1
• RGS14
• Learning
• Memory

Kaynakça

1. 1. Ansel A, Rosenzweig JP, Zisman PD, Melamed M, Gesundheit B. Variation in gene expression in autism spectrum disorders: an extensive review of transcriptomic studies. Front. Neurosci. 2017; 10:601. https://doi.org/10.3389/fnins.2016.00601
2. 2. Charman T, Bair G. Practitioner review: Diagnosis of autism spectrum disorder in 2‐and 3‐year‐old children. J Child Psychol Psychiatry. 2002;43(3):289-305. https://doi.org/10.1111/1469-7610.00022
3. 3. Jacobs D, Steyaert J, Dierickx K, Hens K. Physician view and experience of the diagnosis of autism spectrum disorder in young children. Front. Psychiatry. 2019; 10:372. https://doi.org/10.3389/fpsyt.2019.00372
4. 4. Rao PA, Beidel DC, Murray MJ. Social skills interventions for children with Asperger’s syndrome or high-functioning autism: A review and recommendations. J Autism Dev Disord. 2008;38(2):353-361. https://doi.org/10.1007/s10803-007-0402-4
5. 5. American Psychiatric Association, D. S., & American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5 (Vol. 5). Washington, DC: American psychiatric association.2013
6. 6. Misra V. The social brain network and autism. Ann Neurosci. 2014;21(2):69. https://doi.org/10.5214/ans.0972.7531.210208
7. 7. Goh S, Peterson BS. Imaging evidence for disturbances in multiple learning and memory systems in persons with autism spectrum disorders. Dev Med Child Neurol. 2012;54(3): 208-213. https://doi.org/10.1111/j.1469-8749.2011.04153.x
8. 8. Landsiedel J, Williams DM, Abbot-Smith K. A meta-analysis and critical review of prospective memory in autism spectrum disorder. J Autism Dev Disord.2017;47(3): 646-666. https://doi.org/10.1007/s10803-016-2987-y

9. 9. Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell.2014;157(1): 163-186. https://doi.org/10.1016/j.cell.2014.03.001
10. 10. Kozlov E, Shidlovskii YV, Gilmutdinov R, Schedl P, Zhukova M. The role of CPEB family proteins in the nervous system function in the norm and pathology. Cell Biosci. 2021;11(1):1-14. https://doi.org/10.1186/s13578-021-00577-6
11. 11. Qu WR, Sun QH, Liu QQ, Jin HJ, Cui RJ, Yang W et al. Role of CPEB3 protein in learning and memory: new insights from synaptic plasticity. Aging. 2020;12(14): 15169. https://doi.org/10.18632/aging.103404
12. 12. Parras A, Anta H, Santos-Galindo M, Swarup V, Elorza A, Nieto-González JL et al. Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis- splicing. Nature.2018;560(7719):441-446. https://doi.org/10.1038/s41586-018-0423-5
13. 13. Ivshina M, Lasko P, Richter JD. Cytoplasmic polyadenylation element binding proteins in development, health, and disease. Annu Rev Cell Dev Biol. 2014; 30:393-415. https://doi.org/10.1146/annurev-cellbio-101011-155831
14. 14. Pavlopoulos E, Trifilieff P, Chevaleyre V, Fioriti L, Zairis S, Pagano A et al. Neuralized1 activates CPEB3: a function for nonproteolytic ubiquitin in synaptic plasticity and memory storage. Cell. 2011;147(6):1369-1383. https://doi.org/10.1016/j.cell.2011.09.056
15. 15. Chao HW, Tsai LY, Lu YL, Lin PY, Huang WH, Chou HJ et al. Deletion of CPEB3 enhances hippocampus-dependent memory via increasing expressions of PSD95 and NMDA receptors. J. Neurosci. 2013;33(43):17008-17022. https://doi.org/10.1523/JNEUROSCI.3043-13.2013
16. 16. Taal K, Tuvikene J, Rullinkov G, Piirsoo M, Sepp M, Neuman T et al. Neuralized family member NEURL1 is a ubiquitin ligase for the cGMP-specific phosphodiesterase 9A. Sci Rep. 2019; 9(1): 1-12. https://doi.org/10.1038/s41598-019-43069-x
17. 17. Fioriti L, Myers C, Huang YY, Li X, Stephan JS, Trifilieff P et al. The persistence of hippocampal-based memory requires protein synthesis mediated by the prion-like protein CPEB3. Neuron. 2015;86(6):1433-1448. https://doi.org/10.1016/j.neuron.2015.05.021
18. 18. Lee SE, Simons SB, Heldt SA, Zhao M, Schroeder JP, Vellano CP et al. RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc Natl Acad Sci U S A. 2010;107(39):16994-16998. https://doi.org/10.1073/pnas.1005362107
19. 19. Vellano CP, Lee SE, Dudek SM, Hepler JR. RGS14 at the interface of hippocampal signaling and synaptic plasticity. Trends Pharmacol Sci. 2011;32(11):666-674. https://doi.org/10.1016/j.tips.2011.07.005
20. 20. Squires KE, Gerber KJ, Pare JF, Branch MR, Smith Y, Hepler JR. Regulator of G protein signaling 14 (RGS14) is expressed pre-and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain. Brain Struct Funct. 2018;223(1): 233-253. https://doi.org/10.1007/s00429-017-1487-y
21. 21. Zhang Z, Peng P, Zhang D. Executive Function in High-Functioning Autism Spectrum Disorder: A Meta-analysis of fMRI Studies. J Autism Dev Disord. 2020;50(11). https://doi.org/10.1007/s10803-020-04461-z
22. 22. Gąssowska-Dobrowolska M, Kolasa-Wołosiuk A, Cieślik M, Dominiak A, Friedland K, Adamczyk A. Alterations in tau protein level and phosphorylation state in the brain of the autistic-like rats induced by prenatal exposure to valproic acid. Int. J. Mol. Sci. 2021;22(6):3209. https://doi.org/10.3390/ijms22063209
23. 23. Evans PR, Parra-Bueno P, Smirnov MS, Lustberg DJ, Dudek SM, Hepler JR et al. RGS14 restricts plasticity in hippocampal CA2 by limiting postsynaptic calcium signaling. eNeuro. 2018;5(3). http://dx.doi.org/10.1523/ENEURO.0353-17.2018
24. 24. Vogler C, Spalek K, Aerni A, Demougin P, Müller A, Huynh KD, Papassotiropoulos A, Quervain D. CPEB3 is associated with human episodic memory. Front. Behav. Neurosci. 2009; 3:4. https://doi.org/10.3389/neuro.08.004.2009
25. 25. Pavlopoulos E, Anezaki M, Skoulakis EM. Neuralized is expressed in the α/β lobes of adult Drosophila mushroom bodies and facilitates olfactory long-term memory formation. Proc Natl Acad Sci U S A. 2008;105(38):14674-14679. https://doi.org/10.1073/pnas.0801605105