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

被引：47

作者：

Chakrabarti, Lisa ^{[2
]}

Zahra, Rabaab ^{[1
]}

Jackson, Stephen M. ^{[3
]}

Kazemi-Esfarjani, Parsa ^{[1
]}

Sopher, Bryce L. ^{[3
]}

Mason, Amanda G. ^{[1
]}

Toneff, Thomas ^{[4
]}

Ryu, Soyoung ^{[5
]}

Shaffer, Scott ^{[5
]}

Kansy, Janice W. ^{[1
]}

Eng, Jeremiah ^{[3
]}

Merrihew, Gennifer ^{[6
]}

MacCoss, Michael J. ^{[6
]}

Murphy, Anne ^{[7
]}

Goodlett, David R. ^{[5
]}

Hook, Vivian ^{[4
]}

Bennett, Craig L. ^{[1
]}

Pallanck, Leo J. ^{[6
]}

La Spada, Albert R. ^{[1
,8
,9
]}

机构：

[1] Univ Calif San Diego, Dept Pediat, Div Genet, Rady Childrens Hosp, La Jolla, CA 92093 USA

[2] Univ Nottingham, Sch Med, Sch Biomed Sci, Nottingham NG7 2UH, England

[3] Univ Washington, Med Ctr, Dept Lab Med, Seattle, WA 98195 USA

[4] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA

[5] Univ Washington, Med Ctr, Dept Med Chem, Seattle, WA 98195 USA

[6] Univ Washington, Med Ctr, Dept Genome Sci, Seattle, WA 98195 USA

[7] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[8] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA

来源：

NEURON | 2010年 / 66卷 / 06期

关键词：

SHOTGUN PROTEOMICS; COMPLEX-I; DROSOPHILA; FISSION; DISEASE; MOUSE; CARBOXYPEPTIDASES; NEURODEGENERATION; EXPRESSION; MITOPHAGY;

D O I：

10.1016/j.neuron.2010.05.024

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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.

引用

页码：835 / 847

页数：13

共 39 条

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