Universität zu Köln

Upadhyay, Aaradhita, Hosseinibarkooie, Seyyedmohsen, Schneider, Svenja, Kaczmarek, Anna, Torres-Benito, Laura, Mendoza-Ferreira, Natalia, Overhoff, Melina, Rombo, Roman, Grysko, Vanessa, Kye, Min Jeong ORCID: 0000-0002-1323-7256, Kononenko, Natalia L. and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2019). Neurocalcin Delta Knockout Impairs Adult Neurogenesis Whereas Half Reduction Is Not Pathological. Front. Molec. Neurosci., 12. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1662-5099

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Abstract

Neurocalcin delta (NCALD) is a brain-enriched neuronal calcium sensor and its reduction acts protective against spinal muscular atrophy (SMA). However, the physiological function of NCALD and implications of NCALD reduction are still elusive. Here, we analyzed the ubiquitous Ncald knockout in homozygous (Ncald(KO/KO)) and heterozygous (Ncald(KO/WT)) mice to unravel the physiological role of NCALD in the brain and to study whether 50% NCALD reduction is a safe option for SMA therapy. We found that Ncald(KO/KO) but not Ncald(KO/WT) mice exhibit significant changes in the hippocampal morphology, likely due to impaired generation and migration of newborn neurons in the dentate gyrus (DG). To understand the mechanism behind, we studied the NCALD interactome and identified mitogen-activated protein kinase kinase kinase 10 (MAP3K10) as a novel NCALD interacting partner. MAP3K10 is an upstream activating kinase of c-Jun N-terminal kinase (JNK), which regulates adult neurogenesis. Strikingly, the JNK activation was significantly upregulated in the Ncald(KO/KO) brains. Contrary, neither adult neurogenesis nor JNK activation were altered by heterozygous Ncald deletion. Taken together, our study identifies a novel link between NCALD and adult neurogenesis in the hippocampus, possibly via a MAP3K10-JNK pathway and emphasizes the safety of using NCALD reduction as a therapeutic option for SMA.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Upadhyay, Aaradhita UNSPECIFIED UNSPECIFIED UNSPECIFIED Hosseinibarkooie, Seyyedmohsen UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Svenja UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaczmarek, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Torres-Benito, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Mendoza-Ferreira, Natalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Overhoff, Melina UNSPECIFIED UNSPECIFIED UNSPECIFIED Rombo, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Grysko, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Kye, Min Jeong UNSPECIFIED orcid.org/0000-0002-1323-7256 UNSPECIFIED Kononenko, Natalia L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-156718
DOI:	10.3389/fnmol.2019.00019
Journal or Publication Title:	Front. Molec. Neurosci.
Volume:	12
Date:	2019
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1662-5099
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL MUSCULAR-ATROPHY; HIPPOCAMPAL VOLUME; SHAM CONTROL; PROTEIN; CALCIUM; BRAIN; NUSINERSEN; EXPRESSION; IDENTIFICATION; INHIBITION Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15671