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 activityinduced neurodegeneration and injury-induced axonal degeneration 1,2 . 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 heatshock 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. Injury-induced axonal degeneration is dramatically delayed in wallerian degeneration slow (Wld S ) mice, a mutant strain that over-expresses a chimaeric protein containing the NAD synthase NMNAT 3,4 . The Wld S chimaeric protein offers neuroprotection against axonal degeneration 2,5-7 as well as a variety of neurodegenerative conditions [8][9][10][11] . Wld S protein contains the amino (N)-terminal 70-amino-acid fragment of ubiquitination factor E4B ©2008 Nature Publishing GroupCorrespondence and requests for materials should be addressed to R.G. 4,14,15 . Drosophila contains only one NMNAT gene, whose overexpression delays axonal degeneration 2 . This study and our finding that NMNAT functions as a maintenance factor to protect against activity-induced neurodegeneration 1 suggest that NMNAT alone can protect against multiple neurodegenerative insults. Our recent finding that enzymatically inactive NMNAT retains neuroprotective capabilities also exposed a hitherto unknown molecular function 1 .To test if NMNAT is a general factor required for neuronal maintenance and protection, we first examined the effects of NMNAT overexpression in a Drosophila model for SCA1. Overexpression of wild-type NMNAT or enzyme-inactive NMNAT (NMNAT-WR) 1 suppresses the degenerative phenotypes induced by overexpression of Drosophila ataxin-1 (dAtx-1). It also offers moderate protection against the severe phenotypes caused by overexpression of human ataxin-1 with an expanded (82) poly-glutamine tract (hAtx-1[82Q]) 16 (Fig. 1). These findings, and the observations that NMNAT protects from axonal injury 2 , from photoreceptor injury caused by intense light, and that its loss c...

YCL047C/POF1 Is a Novel Nicotinamide Mononucleotide Adenylyltransferase (NMNAT) in Saccharomyces cerevisiae

“…Some eukaryotic NMNATs have been reported to possess cytoprotective functions. For example, chaperone activity that contributes to axonal protection was described for Drosophila NMNAT (37). In yeast, Nma1 and Nma2 have been shown to alleviate proteotoxicity in yeast models of proteinopathies (38).…”

NAD and axon degeneration: From the Wlds gene to neurochemistry

“…Recent studies from Bellen and colleagues showed in Drosophila that Nmnat functions as a chaperone in protecting neuronal degeneration independent of it NAD synthesis activity. 60,61 The author demonstrated that the mutant Drosophila Nmnat, remains only 1% of enzymatic activity, could provide neuroprotection as good as the wild type and both the wild type and mutant Drosophila Nmnat have chaperone activity. This important result leads to the question if mammalian Nmnats also has chaperone activity and if it is required for its axon protection.…”

Nicotinamide Mononucleotide Adenylyltransferase Is a Stress Response Protein Regulated by the Heat Shock Factor/Hypoxia-inducible Factor 1α Pathway

“…Studies in mammalian neurons have also shown that overexpression of NMNAT protects against injury-or stress-induced axonal degeneration (17)(18)(19)(20). The neuroprotective function of NMNAT is in part mediated through its chaperone activity independent of its NAD synthesis function (15). Although the neuronal maintenance and protective effects of NMNAT have been demonstrated, it is unclear how the nmnat gene is regulated in vivo.…”