Neuronopathic Gaucher disease: dysregulated mRNAs and miRNAs in brain pathogenesis and effects of pharmacologic chaperone treatment in a mouse model
| Autor: | Venette Inskeep, Benjamin Liou, Gregory A. Grabowski, Kenneth D.R. Setchell, Yanyan Peng, You-Hai Xu, Manoj K. Pandey, Wujuan Zhang, Nupur Dasgupta, Ying Sun, Mehdi Keddache, Stuart Tinch, Rong-hua Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Eukaryotic Initiation Factor-2
Mitochondrion Biology Glucosylceramides Synaptic Transmission Pathogenesis microRNA Genetics medicine Animals RNA Messenger Molecular Biology Genetics (clinical) PI3K/AKT/mTOR pathway Neurons Gaucher Disease Gene Expression Profiling TOR Serine-Threonine Kinases Neurodegeneration Psychosine Brain General Medicine Articles medicine.disease Molecular biology Axons Cell biology Mitochondria Mice Inbred C57BL Disease Models Animal MicroRNAs medicine.anatomical_structure Phenotype Synaptic plasticity Neuroglia Encephalitis Signal transduction Imino Pyranoses Molecular Chaperones Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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