Universität zu Köln

Rumyantseva, Anastasia, Motori, Elisa and Trifunovic, Aleksandra ORCID: 0000-0002-5472-3517 (2020). DARS2 is indispensable for Purkinje cell survival and protects against cerebellar ataxia. Hum. Mol. Genet., 29 (17). S. 2845 - 2855. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation disorder (LBSL) arises from mutations in mitochondrial aspartyl-tRNA synthetase (DARS2) gene. The disease has a childhood or juvenile-onset and is clinically characterized by cerebellar ataxia, cognitive decline and distinct morphological abnormalities upon magnetic resonance imaging. We previously demonstrated that neurons and not adult myelin-producing cells are specifically sensitive to DARS2 loss, hence likely the primary culprit in LBSL disorder. We used conditional Purkinje cell (PCs)-specific Dars2 deletion to elucidate further the cell-type-specific contribution of this class of neurons to the cerebellar impairment observed in LBSL. We show that DARS2 depletion causes a severe mitochondrial dysfunction concomitant with a massive loss of PCs by the age of 15 weeks, thereby rapidly deteriorating motor skills. Our findings conclusively show that DARS2 is indispensable for PC survival and highlights the central role of neuroinflammation in DARS2-related PC degeneration.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rumyantseva, Anastasia UNSPECIFIED UNSPECIFIED UNSPECIFIED Motori, Elisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED orcid.org/0000-0002-5472-3517 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-320114
DOI:	10.1093/hmg/ddaa176
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	29
Number:	17
Page Range:	S. 2845 - 2855
Date:	2020
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL-CORD INVOLVEMENT; TRANSFER-RNA SYNTHETASES; BRAIN-STEM; MITOCHONDRIAL; LEUKOENCEPHALOPATHY; DEFICIENCY Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32011