title: NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.
abstract: 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.
authors.affiliation: Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|The Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Yousuf O
authors.initials: YO
authors.lastname: Ali
authors.affiliation: Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|The Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Hunter M
authors.initials: HM
authors.lastname: Allen
authors.affiliation: Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Li-Kroeger
authors.affiliation: Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|The Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Dena
authors.identifier: 0000-0002-6158-8878
authors.initials: D
authors.lastname: Bakhshizadehmahmoudi
authors.affiliation: The Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Asante
authors.identifier: 0000-0002-0200-8802
authors.initials: A
authors.lastname: Hatcher
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Cristin
authors.initials: C
authors.lastname: McCabe
authors.affiliation: 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, Massachusetts, United States of America.
authors.forename: Jishu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bjorklund
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Giulio
authors.initials: G
authors.lastname: Taglialatela
authors.affiliation: Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.|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, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neurology, Baylor College of Medicine, Houston, Texas, United States of America.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Howard Hughes Medical Institute (HHMI), Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.affiliation: Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.|The Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Lu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003071:Cognition / Q000502:physiology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D055550:Protein Stability; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; C484008:NMNAT2 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase