Mitochondrial Dysfunction in NnaD Mutant Flies and Purkinje Cell Degeneration Mice Reveals a Role for Nna Proteins in Neuronal Bioenergetics

作者：Chakrabarti Lisa; Zahra Rabaab; Jackson Stephen M; Kazemi Esfarjani Parsa; Sopher Bryce L; Mason Amanda G; Toneff Thomas; Ryu Soyoung; Shaffer Scott; Kansy Janice W; Eng Jeremiah; Merrihew Gennifer; MacCoss Michael J; Murphy Anne; Goodlett David R; Hook Vivian; Bennett Craig L; Pallanck Leo J; La Spada Albert R^*

来源：Neuron, 2010, 66(6): 835-847.

DOI：10.1016/j.neuron.2010.05.024

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.

• 出版日期2010-6-24