Universität zu Köln

Aradjanski, Marijana ORCID: 0000-0001-5797-5413, Dogan, Sukru Anil ORCID: 0000-0002-1800-2923, Lotter, Stephan, Wang, Shuaiyu, Hermans, Steffen, Wibom, Rolf, Rugarli, Elena ORCID: 0000-0002-5782-1067 and Trifunovic, Aleksandra (2017). DARS2 protects against neuroinflammation and apoptotic neuronal loss, but is dispensable for myelin producing cells. Hum. Mol. Genet., 26 (21). S. 4181 - 4190. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease-leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements. Puzzled by the white matter disease phenotypes caused by DARS2 deficiency when numerous other mutations in the genes encoding proteins involved in mitochondrial translation have a detrimental effect predominantly on neurons, we generated transgenic mice in which DARS2 was specifically depleted in forebrain-hippocampal neurons or myelin-producing cells. Our results now provide the first evidence that loss of DARS2 in adult neurons leads to strong mitochondrial dysfunction and progressive loss of cells. In contrast, myelin-producing cells seem to be resistant to cell death induced by DARS2 depletion despite robust respiratory chain deficiency arguing that LBSL might originate from the primary neuronal and axonal defect. Remarkably, our results also suggest a role for early neuroinflammation in the disease progression, highlighting the possibility for therapeutic interventions of this process.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Aradjanski, Marijana UNSPECIFIED orcid.org/0000-0001-5797-5413 UNSPECIFIED Dogan, Sukru Anil UNSPECIFIED orcid.org/0000-0002-1800-2923 UNSPECIFIED Lotter, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Shuaiyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermans, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Wibom, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Rugarli, Elena UNSPECIFIED orcid.org/0000-0002-5782-1067 UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-212846
DOI:	10.1093/hmg/ddx307
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	26
Number:	21
Page Range:	S. 4181 - 4190
Date:	2017
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL-CORD INVOLVEMENT; BRAIN-STEM; DEFICIENCY; LEUKOENCEPHALOPATHY; OLIGODENDROCYTES; MITOCHONDRIA; MUTATIONS; STRESS Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21284