PMID- 26420838
OWN - NLM
STAT- MEDLINE
DCOM- 20160825
LR  - 20211203
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 24
IP  - 24
DP  - 2015 Dec 15
TI  - Neuronopathic Gaucher disease: dysregulated mRNAs and miRNAs in brain 
      pathogenesis and effects of pharmacologic chaperone treatment in a mouse model.
PG  - 7031-48
LID - 10.1093/hmg/ddv404 [doi]
AB  - Defective lysosomal acid beta-glucosidase (GCase) in Gaucher disease causes 
      accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) that distress 
      cellular functions. To study novel pathological mechanisms in neuronopathic 
      Gaucher disease (nGD), a mouse model (4L;C*), an analogue to subacute human nGD, 
      was investigated for global profiles of differentially expressed brain mRNAs 
      (DEGs) and miRNAs (DEmiRs). 4L;C* mice displayed accumulation of GC and GS, 
      activated microglial cells, reduced number of neurons and aberrant mitochondrial 
      function in the brain followed by deterioration in motor function. DEGs and 
      DEmiRs were characterized from sequencing of mRNA and miRNA from cerebral cortex, 
      brain stem, midbrain and cerebellum of 4L;C* mice. Gene ontology enrichment and 
      pathway analysis showed preferential mitochondrial dysfunction in midbrain and 
      uniform inflammatory response and identified novel pathways, axonal guidance 
      signaling, synaptic transmission, eIF2 and mammalian target of rapamycin (mTOR) 
      signaling potentially involved in nGD. Similar analyses were performed with mice 
      treated with isofagomine (IFG), a pharmacologic chaperone for GCase. IFG 
      treatment did not alter the GS and GC accumulation significantly but attenuated 
      the progression of the disease and altered numerous DEmiRs and target DEGs to 
      their respective normal levels in inflammation, mitochondrial function and axonal 
      guidance pathways, suggesting its regulation on miRNA and the associated mRNA 
      that underlie the neurodegeneration in nGD. These analyses demonstrate that the 
      neurodegenerative phenotype in 4L;C* mice was associated with dysregulation of 
      brain mRNAs and miRNAs in axonal guidance, synaptic plasticity, mitochondria 
      function, eIF2 and mTOR signaling and inflammation and provides new insights for 
      the nGD pathological mechanism.
CI  - (c) The Author 2015. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Dasgupta, Nupur
AU  - Dasgupta N
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Xu, You-Hai
AU  - Xu YH
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Li, Ronghua
AU  - Li R
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA, Department of Pediatrics, University of Cincinnati 
      College of Medicine, Cincinnati, OH 45229, USA.
FAU - Peng, Yanyan
AU  - Peng Y
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Pandey, Manoj K
AU  - Pandey MK
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA, Department of Pediatrics, University of Cincinnati 
      College of Medicine, Cincinnati, OH 45229, USA.
FAU - Tinch, Stuart L
AU  - Tinch SL
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Liou, Benjamin
AU  - Liou B
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Inskeep, Venette
AU  - Inskeep V
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Zhang, Wujuan
AU  - Zhang W
AD  - Division of Pathology, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA and.
FAU - Setchell, Kenneth D R
AU  - Setchell KD
AD  - Division of Pathology, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA and Department of Pediatrics, University of Cincinnati 
      College of Medicine, Cincinnati, OH 45229, USA.
FAU - Keddache, Mehdi
AU  - Keddache M
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Grabowski, Gregory A
AU  - Grabowski GA
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA.
FAU - Sun, Ying
AU  - Sun Y
AD  - Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, 
      Cincinnati, OH 45229, USA, Department of Pediatrics, University of Cincinnati 
      College of Medicine, Cincinnati, OH 45229, USA ying.sun@cchmc.org.
LA  - eng
SI  - GEO/GSE67375
GR  - R01 NS086134/NS/NINDS NIH HHS/United States
GR  - UL1 TR001425/TR/NCATS NIH HHS/United States
GR  - R01 DK 36729/DK/NIDDK NIH HHS/United States
GR  - R01 NS 086134/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150929
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Glucosylceramides)
RN  - 0 (Imino Pyranoses)
RN  - 0 (MicroRNAs)
RN  - 0 (Molecular Chaperones)
RN  - 0 (RNA, Messenger)
RN  - 0 (isofagomine)
RN  - 2238-90-6 (Psychosine)
RN  - 52050-17-6 (sphingosyl beta-glucoside)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Axons/metabolism
MH  - Brain/*metabolism/pathology
MH  - Disease Models, Animal
MH  - Encephalitis/metabolism/pathology
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - Gaucher Disease/drug therapy/*genetics/metabolism/pathology
MH  - Gene Expression Profiling
MH  - Glucosylceramides/metabolism
MH  - Imino Pyranoses/*therapeutic use
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/*metabolism
MH  - Mitochondria/metabolism
MH  - Molecular Chaperones/metabolism/*therapeutic use
MH  - Neuroglia/pathology
MH  - Neurons/pathology
MH  - Phenotype
MH  - Psychosine/analogs & derivatives/metabolism
MH  - RNA, Messenger/*metabolism
MH  - Signal Transduction
MH  - Synaptic Transmission
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4654057
EDAT- 2015/10/01 06:00
MHDA- 2016/08/26 06:00
PMCR- 2016/12/15
CRDT- 2015/10/01 06:00
PHST- 2015/08/01 00:00 [received]
PHST- 2015/09/21 00:00 [accepted]
PHST- 2015/10/01 06:00 [entrez]
PHST- 2015/10/01 06:00 [pubmed]
PHST- 2016/08/26 06:00 [medline]
PHST- 2016/12/15 00:00 [pmc-release]
AID - ddv404 [pii]
AID - 10.1093/hmg/ddv404 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2015 Dec 15;24(24):7031-48. doi: 10.1093/hmg/ddv404. Epub 2015 Sep 
      29.