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Autism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K/Akt/GSK-3β pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.

Titel:	Progranulin improves neural development via the PI3K/Akt/GSK-3β pathway in the cerebellum of a VPA-induced rat model of ASD.
Autor/in / Beteiligte Person:	Wang, L ; Chen, J ; Hu, Y ; Liao, A ; Zheng, W ; Wang, X ; Lan, J ; Shen, J ; Wang, S ; Yang, F ; Wang, Y ; Li, Y ; Chen, D
Link:	Zum Volltext
Zeitschrift:	Translational psychiatry, Jg. 12 (2022-03-22), Heft 1, S. 114
Veröffentlichung:	New York, NY : Nature Pub. Group, 2022
Medientyp:	academicJournal
ISSN:	2158-3188 (electronic)
DOI:	10.1038/s41398-022-01875-4
Schlagwort:	Animals Cerebellum Glycogen Synthase Kinase 3 beta Phosphatidylinositol 3-Kinases Progranulins therapeutic use Proto-Oncogene Proteins c-akt Rats Autism Spectrum Disorder chemically induced Autism Spectrum Disorder drug therapy Valproic Acid adverse effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Transl Psychiatry] 2022 Mar 22; Vol. 12 (1), pp. 114. <i>Date of Electronic Publication: </i>2022 Mar 22. MeSH Terms: Autism Spectrum Disorder* / chemically induced ; Autism Spectrum Disorder* / drug therapy ; Valproic Acid* / adverse effects ; Animals ; Cerebellum ; Glycogen Synthase Kinase 3 beta ; Phosphatidylinositol 3-Kinases ; Progranulins / therapeutic use ; Proto-Oncogene Proteins c-akt ; Rats References: Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jul 13;85:23-32. (PMID: 29627508) ; Cerebellum. 2015 Apr;14(2):197-220. (PMID: 25479821) ; Anat Rec. 2002 Aug 1;267(4):261-76. (PMID: 12124904) ; Front Cell Neurosci. 2017 Nov 20;11:359. (PMID: 29209173) ; Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:1-8. (PMID: 30153496) ; Front Neurosci. 2017 Feb 06;11:35. (PMID: 28220059) ; Neuron. 2014 Aug 6;83(3):518-32. (PMID: 25102558) ; Sci Rep. 2017 Mar 16;7:43594. (PMID: 28300056) ; J Histochem Cytochem. 2000 Jul;48(7):999-1009. (PMID: 10858277) ; Cerebellum. 2013 Oct;12(5):778-9. (PMID: 23605188) ; Biochem Soc Trans. 2006 Dec;34(Pt 6):1287-90. (PMID: 17073803) ; Dialogues Clin Neurosci. 2012 Sep;14(3):263-79. (PMID: 23226952) ; J Mol Med (Berl). 2003 Oct;81(10):600-12. (PMID: 12928786) ; Epilepsy Behav. 2009 May;15(1):83-7. (PMID: 19245845) ; Protein Cell. 2010 Jun;1(6):552-62. (PMID: 21204008) ; Dev Med Child Neurol. 2007 Oct;49(10):734-9. (PMID: 17880641) ; J Neurosci. 2017 Apr 12;37(15):4093-4102. (PMID: 28283559) ; Front Behav Neurosci. 2018 Aug 21;12:182. (PMID: 30186123) ; Neurobiol Dis. 2012 Feb;45(2):711-22. (PMID: 22062772) ; Curr Opin Psychiatry. 2015 Mar;28(2):83-90. (PMID: 25602249) ; Int J Dev Neurosci. 2014 Aug;36:13-8. (PMID: 24798024) ; BMC Geriatr. 2014 Jul 10;14:85. (PMID: 25011478) ; Neuroreport. 2001 Apr 17;12(5):929-33. (PMID: 11303762) ; Neuron. 2018 Feb 21;97(4):796-805.e5. (PMID: 29398357) ; Neuroreport. 2015 Sep 30;26(14):877-81. (PMID: 26302163) ; J Comp Neurol. 2010 Oct 1;518(19):3931-47. (PMID: 20737593) ; Mol Neurodegener. 2016 Oct 22;11(1):69. (PMID: 27770818) ; J Neuroinflammation. 2011 Sep 05;8:111. (PMID: 21892962) ; Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10817-22. (PMID: 19509338) ; J Autism Dev Disord. 2010 Oct;40(10):1227-40. (PMID: 20195737) ; Cerebellum. 2014 Feb;13(1):139-50. (PMID: 23964018) ; J Biol Chem. 1998 Aug 7;273(32):19929-32. (PMID: 9685326) ; Int Rev Neurobiol. 2013;113:1-34. (PMID: 24290381) ; Neurobiol Aging. 2011 Dec;32(12):2326.e5-16. (PMID: 21820214) ; Neuropharmacology. 2021 Sep 15;196:108689. (PMID: 34175324) ; PLoS One. 2011;6(6):e21023. (PMID: 21698296) ; Pharmacol Rep. 2012;64(6):1291-304. (PMID: 23406740) ; Int J Dev Neurosci. 2014 Jun;35:35-41. (PMID: 24662006) ; J Autism Dev Disord. 1995 Feb;25(1):1-18. (PMID: 7608030) ; Interne. 1946 Jan;12:38-42. (PMID: 21011952) ; Neurol Clin. 2007 Aug;25(3):683-96, vi. (PMID: 17659185) ; J Neurosci. 2011 Aug 3;31(31):11126-32. (PMID: 21813674) ; J Cell Biol. 2008 Apr 7;181(1):37-41. (PMID: 18378771) ; Curr Opin Neurobiol. 2011 Aug;21(4):565-70. (PMID: 21696944) ; Epilepsy Behav. 2005 Sep;7(2):161-71. (PMID: 16054870) ; Nat Commun. 2016 Jun 30;7:11992. (PMID: 27356620) ; Neurobiol Aging. 2013 Nov;34(11):2541-7. (PMID: 23706646) ; Brain Res. 2011 Mar 22;1380:138-45. (PMID: 20920490) ; J Clin Invest. 2012 Nov;122(11):3955-9. (PMID: 23041626) ; J Cell Biol. 2015 Sep 14;210(6):991-1002. (PMID: 26370502) ; Neurology. 2002 Jul 23;59(2):184-92. (PMID: 12136055) ; Neuroscience. 2017 Jan 6;340:34-47. (PMID: 27984183) ; Neuroscience. 2010 Jan 20;165(2):363-70. (PMID: 19854241) ; Pediatrics. 2007 Sep;120(3):584-93. (PMID: 17766532) ; J Neuroinflammation. 2007 Feb 11;4:7. (PMID: 17291356) ; Curr Opin Neurobiol. 2012 Jun;22(3):522-9. (PMID: 22409856) ; Biochim Biophys Acta Mol Basis Dis. 2017 Nov;1863(11):2727-2745. (PMID: 28720486) ; Neuron. 2010 Nov 18;68(4):654-67. (PMID: 21092856) ; Proc Natl Acad Sci U S A. 2017 May 9;114(19):5029-5034. (PMID: 28438992) ; Acta Neuropathol. 2018 Jul;136(1):1-17. (PMID: 29744576) ; Brain. 2004 Dec;127(Pt 12):2572-83. (PMID: 15329353) ; Front Cell Neurosci. 2019 Oct 04;13:441. (PMID: 31636540) ; Annu Rev Public Health. 2017 Mar 20;38:81-102. (PMID: 28068486) ; Annu Rev Neurosci. 2009;32:413-34. (PMID: 19555291) Substance Nomenclature: 0 (Progranulins) ; 614OI1Z5WI (Valproic Acid) ; EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) ; EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) Entry Date(s): Date Created: 20220323 Date Completed: 20220404 Latest Revision: 20231102 Update Code: 20231215 PubMed Central ID: PMC8941112

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Progranulin improves neural development via the PI3K/Akt/GSK-3β pathway in the cerebellum of a VPA-induced rat model of ASD.