| AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. | |
| | |
MedLine Citation:
|
PMID: 23041622 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia type 28 and spastic ataxia-neuropathy syndrome in humans; however, the pathogenic mechanism is still unclear. AFG3L2 encodes a subunit of the mitochondrial m-AAA protease, previously implicated in quality control of misfolded inner mitochondrial membrane proteins and in regulatory functions via processing of specific substrates. Here, we used a conditional Afg3l2 mouse model that allows restricted deletion of the gene in Purkinje cells (PCs) to shed light on the pathogenic cascade in the neurons mainly affected in the human diseases. We demonstrate a cell-autonomous requirement of AFG3L2 for survival of PCs. Examination of PCs prior to neurodegeneration revealed fragmentation and altered distribution of mitochondria in the dendritic tree, indicating that abnormal mitochondrial dynamics is an early event in the pathogenic process. Moreover, PCs displayed features pointing to defects in mitochondrially encoded respiratory chain subunits at early stages. To unravel the underlying mechanism, we examined a constitutive knockout of Afg3l2, which revealed a decreased rate of mitochondrial protein synthesis associated with impaired mitochondrial ribosome assembly. We therefore propose that defective mitochondrial protein synthesis, leading to early-onset fragmentation of the mitochondrial network, is a central causative factor in AFG3L2-related neurodegeneration. |
| | |
Authors:
|
Eva R Almajan; Ricarda Richter; Lars Paeger; Paola Martinelli; Esther Barth; Thorsten Decker; Nils-Göran Larsson; Peter Kloppenburg; Thomas Langer; Elena I Rugarli |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-10-08 |
Journal Detail:
|
Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Nov |
Date Detail:
|
Created Date: 2012-11-01 Completed Date: 2013-01-15 Revised Date: 2013-02-20 |
Medline Journal Info:
|
Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
|
Languages: eng Pagination: 4048-58 Citation Subset: AIM; IM |
Affiliation:
|
Institute of Zoology, University of Cologne, Cologne, Germany. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
ATP-Dependent Proteases
/
genetics,
metabolism* Animals Cell Survival Humans Intellectual Disability / genetics, metabolism Membrane Proteins / genetics, metabolism Metalloendopeptidases / genetics, metabolism Mice Mice, Knockout Mitochondria / genetics, metabolism* Mitochondrial Proteins / biosynthesis*, genetics Muscle Spasticity / genetics, metabolism Mutation Nerve Tissue Proteins / genetics, metabolism* Optic Atrophy / genetics, metabolism Protein Biosynthesis / physiology* Purkinje Cells Spinocerebellar Ataxias / genetics, metabolism Spinocerebellar Degenerations / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
|
0/Membrane Proteins; 0/Mitochondrial Proteins; 0/Nerve Tissue Proteins; EC 3.4.21.-/ATP-Dependent Proteases; EC 3.4.24.-/Afg3l2 protein, mouse; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.-/m-AAA proteases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple ne...
Next Document: Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma.