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NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.

PLoS biology | 2016

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.

Pubmed ID: 27254664 RIS Download

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: RF1 AG015819
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS086794
  • Agency: NIA NIH HHS, United States
    Id: K08 AG034290
  • Agency: NIA NIH HHS, United States
    Id: P50 AG016574
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048884
  • Agency: NIA NIH HHS, United States
    Id: R01 AG023173
  • Agency: NIA NIH HHS, United States
    Id: R01 AG017917
  • Agency: NIA NIH HHS, United States
    Id: R01 AG042890
  • Agency: NICHD NIH HHS, United States
    Id: P30 HD024064
  • Agency: NIA NIH HHS, United States
    Id: P30 AG010161
  • Agency: NINDS NIH HHS, United States
    Id: T32 NS043124
  • Agency: NIA NIH HHS, United States
    Id: R01 AG011101
  • Agency: NIA NIH HHS, United States
    Id: P30 AG019610
  • Agency: NIA NIH HHS, United States
    Id: R01 AG015819
  • Agency: NIA NIH HHS, United States
    Id: R01 AG030146
  • Agency: NINDS NIH HHS, United States
    Id: U24 NS051872
  • Agency: NIA NIH HHS, United States
    Id: K01 AG024079
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NIA NIH HHS, United States
    Id: U01 AG016976
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS059873
  • Agency: NIA NIH HHS, United States
    Id: R01 AG023193

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