Abstract
Autism spectrum disorder (ASD) includes a number of severe neurodevelopmental disorders known by defects in social interaction, impaired verbal and non-verbal interactions, and stereotypic activities and limited interests. Dysregulation of apoptotic pathways have been demonstrated in brain tissues of affected individuals. In the present study, we evaluated expression levels of apoptosis-related genes and miRNAs in peripheral blood of ASD patients compared with healthy subjects. Transcript levels of BCL2, CASP8, and hsa-29c-3p were significantly lower in total ASD patients compared with total normal children (P values = 0.003, 0.002, and 0.01 respectively). When sex of study participants was considered in the analysis, the difference in transcript levels of these genes was significant only in male subjects. Peripheral expression of BCL2 and hsa-29c-3p had 100% sensitivity 92% specificity in ASD diagnosis. The diagnostic power of combination of transcript levels of these genes was estimated to be 78% based on the calculated AUC value. The present study provides evidences for dysregulation of apoptotic pathways in peripheral blood of ASD patients and suggests certain apoptosis-related genes as biomarkers in this regard.
Similar content being viewed by others
References
Amaral DG, Schumann CM, Nordahl CW (2008) Neuroanatomy of autism trends. Neuroscience 31:137–145. https://doi.org/10.1016/j.tins.2007.12.005
Araghi-Niknam M, Fatemi SH (2003) Levels of Bcl-2 and P53 are altered in superior frontal and cerebellar cortices of autistic subjects. Cell Mol Neurobiol 23:945–952
Association AP (2013) Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub
Bauman M, Kemper TL (1985) Histoanatomic observations of the brain in early infantile. Autism Neurol 35:866–874. https://doi.org/10.1212/Wnl.35.6.866
Bauman ML, Kemper TL (2005) Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci 23:183–187. https://doi.org/10.1016/j.ijdevneu.2004.09.006
Creemers EE, Tijsen AJ, Pinto YM (2012) Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 110:483–495. https://doi.org/10.1161/circresaha.111.247452
Cristiano C, Lama A, Lembo F, Mollica MP, Calignano A, Mattace Raso G (2018) Interplay between peripheral and central inflammation in autism spectrum disorders: possible nutritional and therapeutic strategies. Front Physiol 9:184. https://doi.org/10.3389/fphys.2018.00184
Desjobert C et al (2011) MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression. Blood 117:6627–6637. https://doi.org/10.1182/blood-2010-09-301994
Dong D, Zielke HR, Yeh D, Yang P (2018) Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder. Autism Res. https://doi.org/10.1002/aur.1966
Egaas B, Courchesne E, Saitoh O (1995) Reduced-size of corpus-callosum in autism arch. Neurol-Chicago 52:794–801. https://doi.org/10.1001/archneur.1995.00540320070014
Espin-Perez A et al (2018) Short-term transcriptome and microRNAs responses to exposure to different air pollutants in two population studies. Environ Pollut (barking, Essex : 1987) 242:182–190. https://doi.org/10.1016/j.envpol.2018.06.051
Fatemi SH, Stary JM, Halt AR, Realmuto GR (2001) Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord 31:529–535
Huang G, Nishimoto K, Zhou Z, Hughes D, Kleinerman ES (2012) miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression. Cancer Res 72:908–916. https://doi.org/10.1158/0008-5472.can-11-1460
Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH (2004) Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry 161:109–115. https://doi.org/10.1176/appi.ajp.161.1.109
Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA (2005) Apoptotic mechanisms in the pathophysiology of schizophrenia. Prog Neuro-Psychoph 29:846–858. https://doi.org/10.1016/j.pnpbp.2005.03.010
Jothiramajayam M, Sinha S, Ghosh M, Nag A, Jana A, Mukherjee A (2014) Sodium fluoride promotes apoptosis by generation of reactive oxygen species in human lymphocytes. J Toxicol Environ Health A 77:1269–1280. https://doi.org/10.1080/15287394.2014.928658
Kamikubo Y, Takasugi N, Niisato K, Hashimoto Y, Sakurai T (2017) Consecutive analysis of BACE1 function on developing and developed neuronal cells. J Alzheimer's Dis 56:641–653. https://doi.org/10.3233/jad-160806
Kichukova TM, Popov NT, Ivanov IS, Vachev TI (2017) Profiling of circulating serum microRNAs in children with autism spectrum disorder using stem-loop qRT-PCR Assay. Folia Med 59:43–52. https://doi.org/10.1515/folmed-2017-0009
Malik M, Sheikh AM, Wen G, Spivack W, Brown WT, Li X (2011) Expression of inflammatory cytokines, Bcl2 and cathepsin D are altered in lymphoblasts of autistic subjects. Immunobiology 216:80–85. https://doi.org/10.1016/j.imbio.2010.03.001
Nazeer A, Ghaziuddin M (2012) Autism Spectrum disorders: clinical features and diagnosis. Pediatr Clin N Am 59:19. https://doi.org/10.1016/j.pcl.2011.10.007
Peng CM, Ma JL, Gao X, Tian P, Li WZ, Zhang L (2013) High glucose induced oxidative stress and apoptosis in cardiac microvascular endothelial cells are regulated by FoxO3a. Plos One 8:e79739. https://doi.org/10.1371/journal.pone.0079739
Petinou K, Minaidou D (2017) Neurobiological bases of autism spectrum disorders and implications for early intervention: a brief overview. Folia Phoniatr Logop 69:38–42. https://doi.org/10.1159/000479181
Roth KA, D’Sa C (2001) Apoptosis and brain development. Ment Retard Dev Disabil Res Rev 7:261–266. https://doi.org/10.1002/mrdd.1036
Sasaki T et al (2006) Bcl2 enhances survival of newborn neurons in the normal and ischemic hippocampus. J Neurosci Res 84:1187–1196. https://doi.org/10.1002/jnr.21036
Schumann CM et al (2004) The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci 24:6392–6401
Sheikh AM, Li X, Wen G, Tauqeer Z, Brown WT, Malik M (2010a) Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects. Neuroscience 165:363–370. https://doi.org/10.1016/j.neuroscience.2009.10.035
Sheikh AM et al (2010b) BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res 88:2641–2647. https://doi.org/10.1002/jnr.22416
Shenker BJ, Guo TL, Shapiro IM (2000) Mercury-induced apoptosis in human lymphoid cells: evidence that the apoptotic pathway is mercurial species dependent. Environ Res 84:89–99. https://doi.org/10.1006/enrs.2000.4078
Siniscalco D, Sapone A, Giordano C, Cirillo A, de Novellis V, de Magistris L, Rossi F, Fasano A, Maione S, Antonucci N (2012) The expression of caspases is enhanced in peripheral blood mononuclear cells of autism spectrum disorder patients. J Autism Dev Disord 42:1403–1410. https://doi.org/10.1007/s10803-011-1373-z
Steiner AM, Goldsmith TR, Snow AV, Chawarska K (2012) Practitioner's guide to assessment of autism spectrum disorders in infants and toddlers. J Autism Dev Disord 42:1183–1196. https://doi.org/10.1007/s10803-011-1376-9
Sullivan PF, Fan C, Perou CM (2006) Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 141B:261–268. https://doi.org/10.1002/ajmg.b.30272
Vaccaro TDS, Sorrentino JM, Salvador S, Veit T, Souza DO, de Almeida RF (2018) Alterations in the MicroRNA of the blood of autism Spectrum disorder patients: effects on epigenetic regulation and potential biomarkers. Behav Sci (Basel, Switzerland) 8. https://doi.org/10.3390/bs8080075
Van Wijngaarden-Cremers PJ, van Eeten E, Groen WB, Van Deurzen PA, Oosterling IJ, Van der Gaag RJ (2014) Gender and age differences in the core triad of impairments in autism spectrum disorders: a systematic review and meta-analysis. J Autism Dev Disord 44:627–635. https://doi.org/10.1007/s10803-013-1913-9
Venkatadri R, Muni T, Iyer AKV, Yakisich JS, Azad N (2016) Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death Cell Death Dis 7 E2104 https://doi.org/10.1038/Cddis.2016.6
Wei H, Alberts I, Li X (2014) The apoptotic perspective of autism. Int J Dev Neurosci 36:13–18. https://doi.org/10.1016/j.ijdevneu.2014.04.004
Wu D, Jose JV, Nurnberger JI, Torres EB (2018) A biomarker characterizing neurodevelopment with applications in autism. Sci rep-Uk 8:614. https://doi.org/10.1038/s41598-017-18902-w
Yun YP, Lee JY, Ahn EK, Lee KH, Yoon HK, Lim Y (2009) Diesel exhaust particles induce apoptosis via p53 and Mdm2 in J774A.1 macrophage cell line. Toxicology In Vitro 23:21–28. https://doi.org/10.1016/j.tiv.2008.09.018
Zong Y et al (2011) miR-29c regulates BACE1 protein expression. Brain Res 1395:108–115. https://doi.org/10.1016/j.brainres.2011.04.035
Zuo HY et al (2014) Neural cell apoptosis induced by microwave exposure through mitochondria-dependent caspase-3 pathway. Int J Med Sci 11:426–435. https://doi.org/10.7150/ijms.6540
Acknowledgements
The current study was supported by a grant from Hamadan University of Medical Sciences.
Funding
This study was financially supported by Hamadan University of Medical Sciences (Grant Number 961177275).
Author information
Authors and Affiliations
Contributions
SGF wrote the manuscript. VKO analyzed the data. MT and AK supervised the study. MME and AN performed the laboratory tests. All authors contributed to and have approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Eftekharian, M.M., Komaki, A., Oskooie, V.K. et al. Assessment of Apoptosis Pathway in Peripheral Blood of Autistic Patients. J Mol Neurosci 69, 588–596 (2019). https://doi.org/10.1007/s12031-019-01387-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-019-01387-9