Year-end Sale % OFF 
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.
Highlights
Robust neuronal maintenance mechanisms are required to minimize or repair damage arising from intrinsic and extrinsic stressors
We found that in humans, levels of Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) transcript are positively correlated with cognitive function and are negatively correlated with pathological features of neurodegenerative disease like plaques and tangles
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)
Summary
Robust neuronal maintenance mechanisms are required to minimize or repair damage arising from intrinsic and extrinsic stressors. Nicotinamide mononucleotide adenylyl transferases (NMNATs) play important roles in neuronal maintenance in flies [1,2] and human [3,4,5,6], and their overexpression provides neuroprotection in diverse neurodegenerative models [7,8]. The literature regarding the importance of this enzymatic activity in axonal health is mixed [8]. NMNAT enzymatic activity is not required to maintain neural integrity in Drosophila photoreceptors [2], suggesting that NMNATs may protect neurons by different mechanisms in a context-dependent manner [7,8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
