NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies

Overview

Journal PLoS Biol

Specialty Biology

Date 2016 Jun 3

PMID 27254664

Citations 77

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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