title: The amyloid-β-SDR5C1(ABAD) interaction does not mediate a specific inhibition of mitochondrial RNase P.
abstract: The amyloid-β peptide (Aβ) is suggested to cause mitochondrial dysfunction in Alzheimer's disease. The mitochondrial dehydrogenase SDR5C1 (also known as ABAD) was shown to bind Aβ and was proposed to thereby mediate mitochondrial toxicity, but the molecular mechanism has not been clarified. We recently identified SDR5C1 as an essential component of human mitochondrial RNase P and its associated tRNA:m¹R9 methyltransferase, the enzymes responsible for tRNA 5'-end processing and methylation of purines at tRNA position 9, respectively. With this work we investigated whether SDR5C1's role as a subunit of these two tRNA-maturation activities represents the mechanistic link between Aβ and mitochondrial dysfunction. Using recombinant enzyme components, we tested RNase P and methyltransferase activity upon titration of Aβ. Micromolar concentrations of monomeric or oligomerized Aβ were required to inhibit tRNA 5'-end processing and position 9 methylation catalyzed by the SDR5C1-containing enzymes, yet similar concentrations of Aβ also inhibited related RNase P and methyltransferase activities, which do not contain an SDR5C1 homolog. In conclusion, the proposed deleterious effect of Aβ on mitochondrial function cannot be explained by a specific inhibition of mitochondrial RNase P or its tRNA:m¹R9 methyltransferase subcomplex, and the molecular mechanism of SDR5C1-mediated Aβ toxicity remains unclear.
authors.affiliation: Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vilardo
authors.forename: Walter
authors.initials: W
authors.lastname: Rossmanith
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D008928:Mitochondria / Q000201:enzymology; D010446:Peptide Fragments / Q000737:chemistry*; D012354:RNA, Transfer, His / Q000737:chemistry; D043262:Ribonuclease P / Q000737:chemistry*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D012359:tRNA Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012354:RNA, Transfer, His; D029701:Saccharomyces cerevisiae Proteins; C075222:amyloid beta-protein (1-42); D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D008780:Methyltransferases; C568603:TRM10 protein, S cerevisiae; C578375:TRMT10c protein, human; D012359:tRNA Methyltransferases; D043262:Ribonuclease P