Frontiers in Molecular Neuroscience (Feb 2019)
Neurocalcin Delta Knockout Impairs Adult Neurogenesis Whereas Half Reduction Is Not Pathological
- Aaradhita Upadhyay,
- Aaradhita Upadhyay,
- Aaradhita Upadhyay,
- Seyyedmohsen Hosseinibarkooie,
- Seyyedmohsen Hosseinibarkooie,
- Seyyedmohsen Hosseinibarkooie,
- Svenja Schneider,
- Svenja Schneider,
- Svenja Schneider,
- Anna Kaczmarek,
- Anna Kaczmarek,
- Anna Kaczmarek,
- Laura Torres-Benito,
- Laura Torres-Benito,
- Laura Torres-Benito,
- Natalia Mendoza-Ferreira,
- Natalia Mendoza-Ferreira,
- Natalia Mendoza-Ferreira,
- Melina Overhoff,
- Melina Overhoff,
- Roman Rombo,
- Roman Rombo,
- Roman Rombo,
- Vanessa Grysko,
- Vanessa Grysko,
- Vanessa Grysko,
- Min Jeong Kye,
- Natalia L. Kononenko,
- Natalia L. Kononenko,
- Brunhilde Wirth,
- Brunhilde Wirth,
- Brunhilde Wirth,
- Brunhilde Wirth
Affiliations
- Aaradhita Upadhyay
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Aaradhita Upadhyay
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Aaradhita Upadhyay
- Institute for Genetics, University of Cologne, Cologne, Germany
- Seyyedmohsen Hosseinibarkooie
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Seyyedmohsen Hosseinibarkooie
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Seyyedmohsen Hosseinibarkooie
- Institute for Genetics, University of Cologne, Cologne, Germany
- Svenja Schneider
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Svenja Schneider
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Svenja Schneider
- Institute for Genetics, University of Cologne, Cologne, Germany
- Anna Kaczmarek
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Anna Kaczmarek
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Anna Kaczmarek
- Institute for Genetics, University of Cologne, Cologne, Germany
- Laura Torres-Benito
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Laura Torres-Benito
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Laura Torres-Benito
- Institute for Genetics, University of Cologne, Cologne, Germany
- Natalia Mendoza-Ferreira
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Natalia Mendoza-Ferreira
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Natalia Mendoza-Ferreira
- Institute for Genetics, University of Cologne, Cologne, Germany
- Melina Overhoff
- Institute for Genetics, University of Cologne, Cologne, Germany
- Melina Overhoff
- Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Roman Rombo
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Roman Rombo
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Roman Rombo
- Institute for Genetics, University of Cologne, Cologne, Germany
- Vanessa Grysko
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Vanessa Grysko
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Vanessa Grysko
- Institute for Genetics, University of Cologne, Cologne, Germany
- Min Jeong Kye
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Natalia L. Kononenko
- Institute for Genetics, University of Cologne, Cologne, Germany
- Natalia L. Kononenko
- Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Brunhilde Wirth
- Institute of Human Genetics, University of Cologne, Cologne, Germany
- Brunhilde Wirth
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Brunhilde Wirth
- Institute for Genetics, University of Cologne, Cologne, Germany
- Brunhilde Wirth
- Center for Rare Diseases Cologne, University Hospital of Cologne, Cologne, Germany
- DOI
- https://doi.org/10.3389/fnmol.2019.00019
- Journal volume & issue
-
Vol. 12
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 (NcaldKO/KO) and heterozygous (NcaldKO/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 NcaldKO/KO but not NcaldKO/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 NcaldKO/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.
Keywords
- neurocalcin delta
- neuronal calcium sensor
- adult neurogenesis
- MAP3K10
- pJNK activation
- spinal muscular atrophy
