title: NAD+ salvage pathway proteins suppress proteotoxicity in yeast models of neurodegeneration by promoting the clearance of misfolded/oligomerized proteins.
abstract: Increased levels of nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT) act as a powerful suppressor of Wallerian degeneration and ataxin- and tau-induced neurodegeneration in flies and mice. However, the nature of the suppression mechanism/s remains controversial. Here, we show that in yeast models of proteinopathies, overexpression of the NMNAT yeast homologs, NMA1 and NMA2, suppresses polyglutamine (PolyQ) and α-synuclein-induced cytotoxicities. Unexpectedly, overexpression of other genes in the salvage pathway for NAD(+) biosynthesis, including QNS1, NPT1 and PNC1 also protected against proteotoxicity. Our data revealed that in all cases, this mechanism involves extensive clearance of the non-native protein. Importantly, we demonstrate that suppression by NMA1 does not require the presence of a functional salvage pathway for NAD(+) biosynthesis, SIR2 or an active mitochondrial oxidative phosphorylation (OXPHOS) system. Our results imply the existence of histone deacetylase- and OXPHOS-independent crosstalk between the proteins in the salvage pathway for NAD(+) biosynthesis and the proteasome that can be manipulated to achieve cellular protection against proteotoxic stress.
authors: Department of Biochemistry and Molecular Biology and 2Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
authors: Alejandro
authors: A
authors: Ocampo
authors: Jingjing
authors: J
authors: Liu
authors: Antoni
authors: A
authors: Barrientos
mesh_terms: D015870:Gene Expression; D006655:Histone Deacetylases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000096:biosynthesis*; D009536:Niacinamide / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010455:Peptides / Q000235:genetics; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D014855:Wallerian Degeneration / Q000235:genetics / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D010455:Peptides; D051844:alpha-Synuclein; D009243:NAD; D009536:Niacinamide; C097188:polyglutamine; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C038480:nicotinic acid mononucleotide adenylyltransferase; D006655:Histone Deacetylases