title: Neuronopathic Gaucher disease: dysregulated mRNAs and miRNAs in brain pathogenesis and effects of pharmacologic chaperone treatment in a mouse model.
abstract: Defective lysosomal acid β-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.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Nupur
authors.initials: N
authors.lastname: Dasgupta
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: You-Hai
authors.initials: YH
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Pandey
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Tinch
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Liou
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Venette
authors.initials: V
authors.lastname: Inskeep
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA and.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Keddache
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism / Q000473:pathology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005776:Gaucher Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005963:Glucosylceramides / Q000378:metabolism; D050112:Imino Pyranoses / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism / Q000627:therapeutic use*; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D011609:Psychosine / Q000031:analogs & derivatives / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D009435:Synaptic Transmission; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D005963:Glucosylceramides; D050112:Imino Pyranoses; D035683:MicroRNAs; D018832:Molecular Chaperones; D012333:RNA, Messenger; C098432:isofagomine; D011609:Psychosine; C035742:sphingosyl beta-glucoside; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases