Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by ch...

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Main Authors: A. Kaitlyn Victor, Martin Donaldson, Daniel Johnson, Winston Miller, Lawrence T. Reiter
Format: Article
Language:English
Published: Frontiers Media S.A. 2021-10-01
Series:Frontiers in Molecular Neuroscience
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fnmol.2021.747855/full
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author A. Kaitlyn Victor
A. Kaitlyn Victor
Martin Donaldson
Daniel Johnson
Winston Miller
Lawrence T. Reiter
Lawrence T. Reiter
Lawrence T. Reiter
author_facet A. Kaitlyn Victor
A. Kaitlyn Victor
Martin Donaldson
Daniel Johnson
Winston Miller
Lawrence T. Reiter
Lawrence T. Reiter
Lawrence T. Reiter
author_sort A. Kaitlyn Victor
collection DOAJ
description Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by chromosome 15 maternal uniparental disomy (PW-UPD). Children with PW-UPD are at higher risk for developing autism spectrum disorder (ASD) than the neurotypical population. In this study, we used expression analysis of PW-UPD neurons to try to identify the molecular cause for increased autism risk.Methods: Dental pulp stem cells (DPSC) from neurotypical control and PWS subjects were differentiated to neurons for mRNA sequencing. Significantly differentially expressed transcripts among all groups were identified. Downstream protein analysis including immunocytochemistry and immunoblots were performed to confirm the transcript level data and pathway enrichment findings.Results: We identified 9 transcripts outside of the PWS critical region (15q11.2-q13.1) that may contribute to core PWS phenotypes. Moreover, we discovered a global reduction in mitochondrial transcripts in the PW-UPD + ASD group. We also found decreased mitochondrial abundance along with mitochondrial aggregates in the cell body and neural projections of +ASD neurons.Conclusion: The 9 transcripts we identified common to all PWS subtypes may reveal PWS specific defects during neurodevelopment. Importantly, we found a global reduction in mitochondrial transcripts in PW-UPD + ASD neurons versus control and other PWS subtypes. We then confirmed mitochondrial defects in neurons from individuals with PWS at the cellular level. Quantification of this phenotype supports our hypothesis that the increased incidence of ASD in PW-UPD subjects may arise from mitochondrial defects in developing neurons.
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spelling doaj.art-d93d90e6be094161a6de3d5657e03ef02022-12-21T20:45:16ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992021-10-011410.3389/fnmol.2021.747855747855Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism SusceptibilityA. Kaitlyn Victor0A. Kaitlyn Victor1Martin Donaldson2Daniel Johnson3Winston Miller4Lawrence T. Reiter5Lawrence T. Reiter6Lawrence T. Reiter7IPBS Program, Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Neurology, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Pediatric Dentistry and Community Oral Health, University of Tennessee Health Science Center, Memphis, TN, United StatesMolecular Bioinformatics Core, University of Tennessee Health Science Center, Memphis, TN, United StatesMolecular Bioinformatics Core, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Neurology, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, United StatesBackground: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by chromosome 15 maternal uniparental disomy (PW-UPD). Children with PW-UPD are at higher risk for developing autism spectrum disorder (ASD) than the neurotypical population. In this study, we used expression analysis of PW-UPD neurons to try to identify the molecular cause for increased autism risk.Methods: Dental pulp stem cells (DPSC) from neurotypical control and PWS subjects were differentiated to neurons for mRNA sequencing. Significantly differentially expressed transcripts among all groups were identified. Downstream protein analysis including immunocytochemistry and immunoblots were performed to confirm the transcript level data and pathway enrichment findings.Results: We identified 9 transcripts outside of the PWS critical region (15q11.2-q13.1) that may contribute to core PWS phenotypes. Moreover, we discovered a global reduction in mitochondrial transcripts in the PW-UPD + ASD group. We also found decreased mitochondrial abundance along with mitochondrial aggregates in the cell body and neural projections of +ASD neurons.Conclusion: The 9 transcripts we identified common to all PWS subtypes may reveal PWS specific defects during neurodevelopment. Importantly, we found a global reduction in mitochondrial transcripts in PW-UPD + ASD neurons versus control and other PWS subtypes. We then confirmed mitochondrial defects in neurons from individuals with PWS at the cellular level. Quantification of this phenotype supports our hypothesis that the increased incidence of ASD in PW-UPD subjects may arise from mitochondrial defects in developing neurons.https://www.frontiersin.org/articles/10.3389/fnmol.2021.747855/fullautism (ASD)mitochondriaPrader-Willi syndrome (PWS)neurodevelopmentdental pulp stem cell (DPSC)mRNA seq
spellingShingle A. Kaitlyn Victor
A. Kaitlyn Victor
Martin Donaldson
Daniel Johnson
Winston Miller
Lawrence T. Reiter
Lawrence T. Reiter
Lawrence T. Reiter
Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility
Frontiers in Molecular Neuroscience
autism (ASD)
mitochondria
Prader-Willi syndrome (PWS)
neurodevelopment
dental pulp stem cell (DPSC)
mRNA seq
title Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility
title_full Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility
title_fullStr Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility
title_full_unstemmed Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility
title_short Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility
title_sort molecular changes in prader willi syndrome neurons reveals clues about increased autism susceptibility
topic autism (ASD)
mitochondria
Prader-Willi syndrome (PWS)
neurodevelopment
dental pulp stem cell (DPSC)
mRNA seq
url https://www.frontiersin.org/articles/10.3389/fnmol.2021.747855/full
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