NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies

Yousuf O. Ali, Hunter M. Allen, Lei Yu, David Li-Kroeger, Dena Bakhshizadehmahmoudi, Asante Hatcher, Cristin McCabe, Jishu Xu, Nicole Bjorklund, Giulio Taglialatela, David A. Bennett, Philip L. De Jager, Joshua M. Shulman, Hugo J. Bellen, Hui Chen Lu

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43 Scopus citations

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.

Original languageEnglish (US)
Article numbere1002472
JournalPLoS biology
Volume14
Issue number6
DOIs
StatePublished - Jun 2 2016

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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. (2016). NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies. PLoS biology, 14(6), [e1002472]. https://doi.org/10.1371/journal.pbio.1002472