Universität zu Köln

Nemeth, Christina L., Tomlinson, Sophia N., Rosen, Melissa, O'Brien, Brett M., Larraza, Oscar, Jain, Mahim, Murray, Connor F., Marx, Joel S., Delannoy, Michael, Fine, Amena S., Wu, Dan, Trifunovic, Aleksandra and Fatemi, Ali (2020). Neuronal ablation of mt-AspRS in mice induces immune pathway activation prior to severe and progressive cortical and behavioral disruption. Exp. Neurol., 326. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1090-2430

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Abstract

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, slowly progressive white matter disease caused by mutations in the mitochondrial aspartyl-tRNA synthetase (mt-AspRS, or DARS2). While patients show characteristic MRI T2 signal abnormalities throughout the cerebral white matter, brainstem, and spinal cord, the phenotypic spectrum is broad and a multitude of gene variants have been associated with the disease. Here, Dars2 disruption in CamKII alpha-expressing cortical and hippocampal neurons results in slowly progressive increases in behavioral activity at five months, and culminating by nine months as severe brain atrophy, behavioral dysfunction, reduced corpus callosum thickness, and microglial morphology indicative of neuroinflammation. Interestingly, RNAseq based gene expression studies performed prior to the presentation of this severe phenotype reveal the upregulation of several pathways involved in immune activation, cytokine production and signaling, and defense response regulation. RNA transcript analysis demonstrates that activation of immune and cell stress pathways are initiated in advance of a behavioral phenotype and cerebral deficits. An understanding of these pathways and their contribution to significant neuronal loss in CamKII-Dars2 deficient mice may aid in deciphering mechanisms of LBSL pathology.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nemeth, Christina L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tomlinson, Sophia N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosen, Melissa UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Brien, Brett M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Larraza, Oscar UNSPECIFIED UNSPECIFIED UNSPECIFIED Jain, Mahim UNSPECIFIED UNSPECIFIED UNSPECIFIED Murray, Connor F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marx, Joel S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Delannoy, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Fine, Amena S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Dan UNSPECIFIED UNSPECIFIED UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Fatemi, Ali UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-339837
DOI:	10.1016/j.expneurol.2019.113164
Journal or Publication Title:	Exp. Neurol.
Volume:	326
Date:	2020
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1090-2430
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL-CORD INVOLVEMENT; TRANSFER-RNA SYNTHETASE; BRAIN-STEM; STRESS-RESPONSE; LACTATE ELEVATION; LEUKOENCEPHALOPATHY; DEFICIENCY; ALPHA; MOUSE; LBSL Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33983