NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies

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.

Abstract

This study reveals NMNAT2 to be a dual-function neuronal maintenance factor that not only generates NAD to protect neurons from excitotoxicity but also moonlights as a chaperone to combat protein toxicity.

Author Summary

Pathological protein aggregates are found in many neurodegenerative diseases, and it has been hypothesized that these protein aggregates are toxic and cause neuronal death. Little is known about how neurons protect against pathological protein aggregates to maintain their health. Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is a newly identified neuronal maintenance factor. We found that in humans, levels of NMNAT2 transcript are positively correlated with cognitive function and are negatively correlated with pathological features of neurodegenerative disease like plaques and tangles. In this study, we demonstrate that NMNAT2 can act as a chaperone to reduce protein aggregates, and this function is independent from its known function in the enzymatic synthesis of nicotinamide adenine dinucleotide (NAD). We find that NMNAT2 interacts with heat shock protein 90 (HSP90) to refold protein aggregates, and that deleting NMNAT2 in cortical neurons renders them vulnerable to protein stress or excitotoxicity. Interestingly, the chaperone function of NMNAT2 protects neurons from protein toxicity, while its enzymatic function is required to defend against excitotoxicity. Our work here suggests that NMNAT2 uses either its chaperone or enzymatic function to combat neuronal insults in a context-dependent manner. In Alzheimer disease brains, NMNAT2 levels are less than 50% of control levels, and we propose that enhancing NMNAT2 function may provide an effective therapeutic intervention to reserve cognitive function.