Universität zu Köln

Almajan, Eva R., Richter, Ricarda, Paeger, Lars ORCID: 0000-0001-8716-3483, Martinelli, Paola, Barth, Esther, Decker, Thorsten, Larsson, Nils-Goeran, Kloppenburg, Peter, Langer, Thomas ORCID: 0000-0003-1250-1462 and Rugarli, Elena I. (2012). AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J. Clin. Invest., 122 (11). S. 4048 - 4059. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Almajan, Eva R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richter, Ricarda UNSPECIFIED UNSPECIFIED UNSPECIFIED Paeger, Lars UNSPECIFIED orcid.org/0000-0001-8716-3483 UNSPECIFIED Martinelli, Paola UNSPECIFIED UNSPECIFIED UNSPECIFIED Barth, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Decker, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Larsson, Nils-Goeran UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloppenburg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED orcid.org/0000-0003-1250-1462 UNSPECIFIED Rugarli, Elena I. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-480557
DOI:	10.1172/JCI64604
Journal or Publication Title:	J. Clin. Invest.
Volume:	122
Number:	11
Page Range:	S. 4048 - 4059
Date:	2012
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language M-AAA PROTEASE; SPASTIC PARAPLEGIA; LARGE SUBUNIT; DYSFUNCTION; EXPRESSION; MUTATIONS; MEMBRANE; RIBOSOME; ATAXIA; MICE Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48055