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Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice.

Fragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here, we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitocho... Full description

Journal Title: Nature neuroscience March 2019, Vol.22(3), pp.386-400
Main Author: Shen, Minjie
Other Authors: Wang, Feifei , Li, Meng , Sah, Nirnath , Stockton, Michael E , Tidei, Joseph J , Gao, Yu , Korabelnikov, Tomer , Kannan, Sudharsan , Vevea, Jason D , Chapman, Edwin R , Bhattacharyya, Anita , van Praag, Henriette , Zhao, Xinyu
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1546-1726 ; DOI: 10.1038/s41593-019-0338-y
Link: http://search.proquest.com/docview/2185555553/?pq-origsite=primo
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title: Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice.
format: Article
creator:
  • Shen, Minjie
  • Wang, Feifei
  • Li, Meng
  • Sah, Nirnath
  • Stockton, Michael E
  • Tidei, Joseph J
  • Gao, Yu
  • Korabelnikov, Tomer
  • Kannan, Sudharsan
  • Vevea, Jason D
  • Chapman, Edwin R
  • Bhattacharyya, Anita
  • van Praag, Henriette
  • Zhao, Xinyu
subjects:
  • Animals–Metabolism
  • Dendrites–Growth & Development
  • Dentate Gyrus–Metabolism
  • Female–Genetics
  • Fragile X Mental Retardation Protein–Metabolism
  • Gene Knockdown Techniques–Genetics
  • Genes, Mitochondrial–Metabolism
  • Huntingtin Protein–Metabolism
  • Male–Metabolism
  • Mice, Inbred C57bl–Metabolism
  • Mice, Knockout–Metabolism
  • Mitochondrial Dynamics–Metabolism
  • Oxidative Stress–Metabolism
  • Fmr1 Protein, Mouse
  • Htt Protein, Mouse
  • Huntingtin Protein
  • Fragile X Mental Retardation Protein
ispartof: Nature neuroscience, March 2019, Vol.22(3), pp.386-400
description: Fragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here, we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress. Enhancing mitochondrial fusion partially rescued dendritic abnormalities in FMRP-deficient immature neurons. We show that FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation. Mice with hippocampal Htt knock-down and Fmr1 knockout mice showed similar behavioral deficits that could be rescued by treatment with a mitochondrial fusion compound. Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of Fragile X syndrome.
language: eng
source:
identifier: E-ISSN: 1546-1726 ; DOI: 10.1038/s41593-019-0338-y
fulltext: fulltext
issn:
  • 15461726
  • 1546-1726
url: Link


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titleReduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice.
creatorShen, Minjie ; Wang, Feifei ; Li, Meng ; Sah, Nirnath ; Stockton, Michael E ; Tidei, Joseph J ; Gao, Yu ; Korabelnikov, Tomer ; Kannan, Sudharsan ; Vevea, Jason D ; Chapman, Edwin R ; Bhattacharyya, Anita ; van Praag, Henriette ; Zhao, Xinyu
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ispartofNature neuroscience, March 2019, Vol.22(3), pp.386-400
identifierE-ISSN: 1546-1726 ; DOI: 10.1038/s41593-019-0338-y
subjectAnimals–Metabolism ; Dendrites–Growth & Development ; Dentate Gyrus–Metabolism ; Female–Genetics ; Fragile X Mental Retardation Protein–Metabolism ; Gene Knockdown Techniques–Genetics ; Genes, Mitochondrial–Metabolism ; Huntingtin Protein–Metabolism ; Male–Metabolism ; Mice, Inbred C57bl–Metabolism ; Mice, Knockout–Metabolism ; Mitochondrial Dynamics–Metabolism ; Oxidative Stress–Metabolism ; Fmr1 Protein, Mouse ; Htt Protein, Mouse ; Huntingtin Protein ; Fragile X Mental Retardation Protein
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descriptionFragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here, we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress. Enhancing mitochondrial fusion partially rescued dendritic abnormalities in FMRP-deficient immature neurons. We show that FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation. Mice with hippocampal Htt knock-down and Fmr1 knockout mice showed similar behavioral deficits that could be rescued by treatment with a mitochondrial fusion compound. Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of Fragile X syndrome.
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authorShen, Minjie ; Wang, Feifei ; Li, Meng ; Sah, Nirnath ; Stockton, Michael E ; Tidei, Joseph J ; Gao, Yu ; Korabelnikov, Tomer ; Kannan, Sudharsan ; Vevea, Jason D ; Chapman, Edwin R ; Bhattacharyya, Anita ; van Praag, Henriette ; Zhao, Xinyu
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