Document Detail

AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival.
MedLine Citation:
PMID:  23041622     Owner:  NLM     Status:  MEDLINE    
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.
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:  2013-07-11    
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    
Institute of Zoology, University of Cologne, Cologne, Germany.
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MeSH Terms
ATP-Dependent Proteases / genetics,  metabolism*
Cell Survival
Intellectual Disability / genetics,  metabolism
Membrane Proteins / genetics,  metabolism
Metalloendopeptidases / genetics,  metabolism
Mice, Knockout
Mitochondria / genetics,  metabolism*
Mitochondrial Proteins / biosynthesis*,  genetics
Muscle Spasticity / genetics,  metabolism
Nerve Tissue Proteins / genetics,  metabolism*
Optic Atrophy / genetics,  metabolism
Protein Biosynthesis / physiology*
Purkinje Cells
Spinocerebellar Ataxias / genetics,  metabolism
Spinocerebellar Degenerations / genetics,  metabolism
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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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