NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies

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NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies

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Title: NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies
Author: Ali, Yousuf O.; Allen, Hunter M.; Yu, Lei; Li-Kroeger, David; Bakhshizadehmahmoudi, Dena; Hatcher, Asante; McCabe, Cristin; Xu, Jishu; Bjorklund, Nicole; Taglialatela, Giulio; Bennett, David A.; De Jager, Philip L.; Shulman, Joshua M.; Bellen, Hugo J.; Lu, Hui-Chen

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Citation: Ali, Y. O., H. M. Allen, L. Yu, D. Li-Kroeger, D. Bakhshizadehmahmoudi, A. Hatcher, C. McCabe, et al. 2016. “NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.” PLoS Biology 14 (6): e1002472. doi:10.1371/journal.pbio.1002472. http://dx.doi.org/10.1371/journal.pbio.1002472.
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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.
Published Version: doi:10.1371/journal.pbio.1002472
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890852/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662098
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