NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.

PLoS Biol
Authors
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.

Year of Publication
2016
Journal
PLoS Biol
Volume
14
Issue
6
Pages
e1002472
Date Published
2016 Jun
ISSN
1545-7885
URL
DOI
10.1371/journal.pbio.1002472
PubMed ID
27254664
PubMed Central ID
PMC4890852
Links
Grant list
R01 NS086794 / NS / NINDS NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States