title: NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration.
abstract: Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activity-induced neurodegeneration and injury-induced axonal degeneration. Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA. gzhai@med.miami.edu
authors.forename: R Grace
authors.initials: RG
authors.lastname: Zhai
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: P Robin
authors.initials: PR
authors.lastname: Hiesinger
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.forename: Claire M
authors.initials: CM
authors.lastname: Haueter
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D019732:Amide Synthases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004330:Drosophila / Q000201:enzymology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D020754:Spinocerebellar Ataxias / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D019732:Amide Synthases; C038479:NAD+ synthase