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NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies
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نویسنده
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ali y.o. ,allen h.m. ,yu l. ,li-kroeger d. ,bakhshizadehmahmoudi d. ,hatcher a. ,mccabe c. ,xu j. ,bjorklund n. ,taglialatela g. ,bennett d.a. ,de jager p.l. ,shulman j.m. ,bellen h.j. ,lu h.-c.
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منبع
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plos biology - 2016 - دوره : 14 - شماره : 6
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چکیده
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Nicotinamide mononucleotide adenylyl transferase 2 (nmnat2) is neuroprotective in numerous preclinical models of neurodegeneration. here,we show that brain nmnat2 mrna levels correlate positively with global cognitive function and negatively with ad pathology. in ad brains,nmnat2 mrna and protein levels are reduced. nmnat2 shifts its solubility and colocalizes with aggregated tau in ad brains,similar to chaperones,which aid in the clearance or refolding of misfolded proteins. investigating the mechanism of this observation,we discover a novel chaperone function of nmnat2,independent from its enzymatic activity. nmnat2 complexes with heat shock protein 90 (hsp90) to refold aggregated protein substrates. nmnat2’s refoldase activity requires a unique c-terminal atp site,activated in the presence of hsp90. furthermore,deleting nmnat2 function increases the vulnerability of cortical neurons to proteotoxic stress and excitotoxicity. interestingly,nmnat2 acts as a chaperone to reduce proteotoxic stress,while its enzymatic activity protects neurons from excitotoxicity. taken together,our data indicate that nmnat2 exerts its chaperone or enzymatic function in a context-dependent manner to maintain neuronal health. © 2016 ali et al.
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آدرس
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linda and jack gill center,department of psychological and brain sciences,indiana university,bloomington,in,united states,the cain foundation laboratories,texas children’s hospital,houston,tx,united states,jan and dan duncan neurological research institute,texas children’s hospital,houston,tx,united states,department of pediatrics,baylor college of medicine,houston,tx, United States, linda and jack gill center,department of psychological and brain sciences,indiana university,bloomington,in,united states,the cain foundation laboratories,texas children’s hospital,houston,tx,united states,jan and dan duncan neurological research institute,texas children’s hospital,houston,tx, United States, rush alzheimer’s disease center and department of neurological sciences,rush university,chicago,il, United States, jan and dan duncan neurological research institute,texas children’s hospital,houston,tx,united states,department of molecular and human genetics,baylor college of medicine,houston,tx, United States, linda and jack gill center,department of psychological and brain sciences,indiana university,bloomington,in,united states,the cain foundation laboratories,texas children’s hospital,houston,tx,united states,jan and dan duncan neurological research institute,texas children’s hospital,houston,tx,united states,department of pediatrics,baylor college of medicine,houston,tx, United States, the cain foundation laboratories,texas children’s hospital,houston,tx,united states,department of neuroscience,baylor college of medicine,houston,tx, United States, program in medical and population genetics,broad institute,cambridge,ma, United States, program in translational neuropsychiatric genomics,institute for the neurosciences,departments of neurology and psychiatry,division of genetics,department of medicine,brigham and women’s hospital,boston,ma, United States, department of neuroscience and cell biology,university of texas medical branch,galveston,tx, United States, department of neuroscience and cell biology,university of texas medical branch,galveston,tx, United States, rush alzheimer’s disease center and department of neurological sciences,rush university,chicago,il, United States, program in medical and population genetics,broad institute,cambridge,ma,united states,program in translational neuropsychiatric genomics,institute for the neurosciences,departments of neurology and psychiatry,division of genetics,department of medicine,brigham and women’s hospital,boston,ma,united states,harvard medical school,boston,ma, United States, jan and dan duncan neurological research institute,texas children’s hospital,houston,tx,united states,department of molecular and human genetics,baylor college of medicine,houston,tx,united states,department of neuroscience,baylor college of medicine,houston,tx,united states,department of neurology,baylor college of medicine,houston,tx,united states,program in developmental biology,baylor college of medicine,houston,tx, United States, jan and dan duncan neurological research institute,texas children’s hospital,houston,tx,united states,department of pediatrics,baylor college of medicine,houston,tx,united states,department of molecular and human genetics,baylor college of medicine,houston,tx,united states,department of neuroscience,baylor college of medicine,houston,tx,united states,program in developmental biology,baylor college of medicine,houston,tx,united states,howard hughes medical institute (hhmi),baylor college of medicine,houston,tx, United States, linda and jack gill center,department of psychological and brain sciences,indiana university,bloomington,in,united states,the cain foundation laboratories,texas children’s hospital,houston,tx,united states,jan and dan duncan neurological research institute,texas children’s hospital,houston,tx,united states,department of pediatrics,baylor college of medicine,houston,tx,united states,department of neuroscience,baylor college of medicine,houston,tx,united states,program in developmental biology,baylor college of medicine,houston,tx, United States
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Authors
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