Mitochondrial dysfunction in NnaD mutant flies and Purkinje cell degeneration mice reveals a role for Nna proteins in neuronal bioenergetics.


Journal Article

The Purkinje cell degeneration (pcd) mouse is a recessive model of neurodegeneration, involving cerebellum and retina. Purkinje cell death in pcd is dramatic, as >99% of Purkinje neurons are lost in 3 weeks. Loss of function of Nna1 causes pcd, and Nna1 is a highly conserved zinc carboxypeptidase. To determine the basis of pcd, we implemented a two-pronged approach, combining characterization of loss-of-function phenotypes of the Drosophila Nna1 ortholog (NnaD) with proteomics analysis of pcd mice. Reduced NnaD function yielded larval lethality, with survivors displaying phenotypes that mirror disease in pcd. Quantitative proteomics revealed expression alterations for glycolytic and oxidative phosphorylation enzymes. Nna proteins localize to mitochondria, loss of NnaD/Nna1 produces mitochondrial abnormalities, and pcd mice display altered proteolytic processing of Nna1 interacting proteins. Our studies indicate that Nna1 loss of function results in altered bioenergetics and mitochondrial dysfunction.

Full Text

Duke Authors

Cited Authors

  • Chakrabarti, L; Zahra, R; Jackson, SM; Kazemi-Esfarjani, P; Sopher, BL; Mason, AG; Toneff, T; Ryu, S; Shaffer, S; Kansy, JW; Eng, J; Merrihew, G; MacCoss, MJ; Murphy, A; Goodlett, DR; Hook, V; Bennett, CL; Pallanck, LJ; La Spada, AR

Published Date

  • June 24, 2010

Published In

Volume / Issue

  • 66 / 6

Start / End Page

  • 835 - 847

PubMed ID

  • 20620870

Pubmed Central ID

  • 20620870

Electronic International Standard Serial Number (EISSN)

  • 1097-4199

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2010.05.024


  • eng

Conference Location

  • United States