NAD+ salvage pathway proteins suppress proteotoxicity in yeast models of neurodegeneration by promoting the clearance of misfolded/oligomerized proteins

Alejandro Ocampo, Jingjing Liu, Antoni Barrientos

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Article numberddt016
Pages (from-to)1699-1708
Number of pages10
JournalHuman molecular genetics
Volume22
Issue number9
DOIs
StatePublished - May 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'NAD<sup>+</sup> salvage pathway proteins suppress proteotoxicity in yeast models of neurodegeneration by promoting the clearance of misfolded/oligomerized proteins'. Together they form a unique fingerprint.

Cite this