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NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies
Yousuf O Ali1,2,3,4, Hunter M Allen1,2,3, Lei Yu5
1Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America.
Plos Biology
|June 3, 2016
Summary
Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) offers neuroprotection by acting as a chaperone to refold proteins and enzymatically protecting neurons. Reduced NMNAT2 levels correlate with cognitive decline and Alzheimer's disease pathology.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is known for its neuroprotective roles in preclinical models.
- Reduced NMNAT2 levels are observed in Alzheimer's disease (AD) brains, correlating with cognitive impairment.
Purpose of the Study:
- To investigate the novel chaperone function of NMNAT2 and its role in neurodegeneration.
- To elucidate the context-dependent mechanisms by which NMNAT2 maintains neuronal health.
Main Methods:
- Correlation analysis of nmnat2 mRNA levels with cognitive function and AD pathology.
- Immunoblotting and immunofluorescence to assess NMNAT2 protein levels and localization in AD brains.
- In vitro assays to study NMNAT2's interaction with HSP90 and its refolding activity.
- Neuronal vulnerability assays assessing proteotoxic and excitotoxic stress.
Main Results:
- Brain nmnat2 mRNA levels positively correlate with cognitive function and negatively with AD pathology.
- NMNAT2 protein and mRNA levels are decreased in AD brains.
- NMNAT2 exhibits a novel, enzymatic activity-independent chaperone function, complexing with HSP90 to refold aggregated proteins.
- Loss of NMNAT2 function increases neuronal vulnerability to proteotoxic and excitotoxic stress.
- NMNAT2's chaperone activity mitigates proteotoxic stress, while its enzymatic activity protects against excitotoxicity.
Conclusions:
- NMNAT2 possesses dual functionality: a chaperone role for proteostasis and an enzymatic role for excitotoxicity protection.
- NMNAT2's neuroprotective effects are context-dependent, highlighting its importance in maintaining neuronal health.
- Therapeutic strategies targeting NMNAT2 could be beneficial for neurodegenerative diseases like AD.
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