Details

Autor(en) / Beteiligte

• Ocampo, Alejandro
• Liu, Jingjing
• Barrientos, Antoni

Titel

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

Ist Teil von

• Human molecular genetics, 2013-05, Vol.22 (9), p.1699-1708

Erscheinungsjahr

2013

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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 alpha -synuclein-induced cytotoxicities. Unexpectedly, overexpression of other genes in the salvage pathway for NAD super(+) 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 super(+) 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 super(+) biosynthesis and the proteasome that can be manipulated to achieve cellular protection against proteotoxic stress.