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1.
J Cereb Blood Flow Metab ; 41(8): 2116-2131, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33563078

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway. Our previous study demonstrated that deletion of NAMPT gene in projection neurons using Thy1-NAMPT-/- conditional knockout (cKO) mice causes neuronal degeneration, muscle atrophy, neuromuscular junction abnormalities, paralysis and eventually death. Here we conducted a combined metabolomic and transcriptional profiling study in vivo in an attempt to further investigate the mechanism of neuronal degeneration at metabolite and mRNA levels after NAMPT deletion. Here using steady-state metabolomics, we demonstrate that deletion of NAMPT causes a significant decrease of NAD+ metabolome and bioenergetics, a buildup of metabolic intermediates upstream of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in glycolysis, and an increase of oxidative stress. RNA-seq shows that NAMPT deletion leads to the increase of mRNA levels of enzymes in NAD metabolism, in particular PARP family of NAD+ consumption enzymes, as well as glycolytic genes Glut1, Hk2 and PFBFK3 before GAPDH. GO, KEGG and GSEA analyses show the activations of apoptosis, inflammation and immune responsive pathways and the inhibition of neuronal/synaptic function in the cKO mice. The current study suggests that increased oxidative stress, apoptosis and neuroinflammation contribute to neurodegeneration and mouse death as a direct consequence of bioenergetic stress after NAMPT deletion.


Assuntos
Morte Celular/genética , Citocinas/genética , Metabolismo Energético/genética , Neurônios/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Estresse Oxidativo/genética , Trifosfato de Adenosina/metabolismo , Animais , Citocinas/deficiência , Regulação para Baixo , Feminino , Glicólise , Masculino , Metabolômica , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/deficiência , Análise de Componente Principal , Regulação para Cima
2.
Cell Rep ; 20(9): 2184-2200, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28854367

RESUMO

Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD+ biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD+ biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.


Assuntos
Envelhecimento/patologia , Deleção de Genes , Córtex Motor/fisiopatologia , Degeneração Neural/enzimologia , Degeneração Neural/patologia , Neurônios/enzimologia , Neurônios/patologia , Nicotinamida Fosforribosiltransferase/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/patologia , Animais , Comportamento Animal , Morte Celular , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Homeostase , Humanos , Camundongos Knockout , Mitocôndrias/metabolismo , Atividade Motora , Córtex Motor/patologia , Atrofia Muscular/patologia , Degeneração Neural/complicações , Degeneração Neural/fisiopatologia , Junção Neuromuscular/enzimologia , Junção Neuromuscular/patologia , Mononucleotídeo de Nicotinamida/uso terapêutico , Transmissão Sináptica
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