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Overexpression of human mutated G93A SOD1 changes dynamics of the ER mitochondria calcium cycle specifically in mouse embryonic motor neurons.
Exp Neurol. 2013 Sep; 247:91-100.EN

Abstract

Motor neurons vulnerable to the rapidly progressive deadly neurodegenerative disease amyotrophic lateral sclerosis (ALS) inherently express low amounts of calcium binding proteins (CaBP), likely to allow physiological motor neuron firing frequency modulation. At the same time motor neurons are susceptible to AMPA receptor mediated excitotoxicity and internal calcium deregulation which is not fully understood. We analysed ER mitochondria calcium cycle (ERMCC) dynamics with subsecond resolution in G93A hSOD1 overexpressing motor neurons as a model of ALS using fluorescent calcium imaging. When comparing vulnerable motor neurons and non-motor neurons from G93A hSOD1 mice and their non-transgenic littermates, we found a decelerated cytosolic calcium clearance in the presence of G93A hSOD1. While both non-transgenic as well as G93A hSOD1 motor neurons displayed large mitochondrial calcium uptake by the mitochondrial uniporter (mUP), the mitochondrial calcium extrusion system was altered in the presence of G93A hSOD1. In addition, ER calcium uptake by the sarco-/endoplasmic reticulum ATPase (SERCA) was increased in G93A hSOD1 motor neurons. In survival assays, blocking the mitochondrial sodium calcium exchanger (mNCE) by CGP37157 as well as inhibiting SERCA by cyclopiazonic acid showed protective effects against kainate induced excitotoxicity. Thus, our study shows for the first time that the functional consequence of G93A hSOD1 overexpression in intact motor neurons is indeed a disturbance of the ER mitochondria calcium cycle, and identified two promising targets for therapeutic intervention in the pathology of ALS.

Authors+Show Affiliations

Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany. janin.lautenschlaeger@med.uni-jena.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23578819

Citation

Lautenschläger, Janin, et al. "Overexpression of Human Mutated G93A SOD1 Changes Dynamics of the ER Mitochondria Calcium Cycle Specifically in Mouse Embryonic Motor Neurons." Experimental Neurology, vol. 247, 2013, pp. 91-100.
Lautenschläger J, Prell T, Ruhmer J, et al. Overexpression of human mutated G93A SOD1 changes dynamics of the ER mitochondria calcium cycle specifically in mouse embryonic motor neurons. Exp Neurol. 2013;247:91-100.
Lautenschläger, J., Prell, T., Ruhmer, J., Weidemann, L., Witte, O. W., & Grosskreutz, J. (2013). Overexpression of human mutated G93A SOD1 changes dynamics of the ER mitochondria calcium cycle specifically in mouse embryonic motor neurons. Experimental Neurology, 247, 91-100. https://doi.org/10.1016/j.expneurol.2013.03.027
Lautenschläger J, et al. Overexpression of Human Mutated G93A SOD1 Changes Dynamics of the ER Mitochondria Calcium Cycle Specifically in Mouse Embryonic Motor Neurons. Exp Neurol. 2013;247:91-100. PubMed PMID: 23578819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of human mutated G93A SOD1 changes dynamics of the ER mitochondria calcium cycle specifically in mouse embryonic motor neurons. AU - Lautenschläger,Janin, AU - Prell,Tino, AU - Ruhmer,Julia, AU - Weidemann,Lisa, AU - Witte,Otto W, AU - Grosskreutz,Julian, Y1 - 2013/04/08/ PY - 2013/01/05/received PY - 2013/03/14/revised PY - 2013/03/28/accepted PY - 2013/4/13/entrez PY - 2013/4/13/pubmed PY - 2013/12/16/medline KW - ALS KW - AMPA KW - Amyotrophic lateral sclerosis KW - CPA KW - CaBP KW - Calcium KW - CsA KW - EMD KW - ER KW - ER mitochondria calcium cycle KW - ERMCC KW - FUS/TLS KW - Mitochondria KW - Motor neuron KW - SERCA KW - TDP-43 KW - TTX KW - UPR KW - VAPB KW - VCP KW - VGCC KW - X-box binding protein 1 KW - XBP1 KW - amyotrophic lateral sclerosis KW - calcium binding proteins KW - cyclopiazonic acid KW - cyclosporine A KW - eIF2α KW - earth mover's distance KW - eukaryotic translation initiation factor 2 α KW - fused in sarcoma/translated in liposarcoma KW - hSOD1 KW - human superoxide dismutase 1 KW - mNCE KW - mPTP KW - mUP KW - mitochondrial permeability transition pore KW - mitochondrial sodium calcium exchanger KW - mitochondrial uniporter KW - sarco-/endoplasmic reticulum ATPase KW - tetrodotoxin KW - transactive response (TAR) DNA-binding protein-43 KW - unfolded protein response KW - valosin containing protein KW - vesicle-associated membrane protein (VAMP)-associated protein B KW - voltage gated calcium channels KW - α-amino-5-methyl-3-hydroxyisoxazolone-4-propionat SP - 91 EP - 100 JF - Experimental neurology JO - Exp Neurol VL - 247 N2 - Motor neurons vulnerable to the rapidly progressive deadly neurodegenerative disease amyotrophic lateral sclerosis (ALS) inherently express low amounts of calcium binding proteins (CaBP), likely to allow physiological motor neuron firing frequency modulation. At the same time motor neurons are susceptible to AMPA receptor mediated excitotoxicity and internal calcium deregulation which is not fully understood. We analysed ER mitochondria calcium cycle (ERMCC) dynamics with subsecond resolution in G93A hSOD1 overexpressing motor neurons as a model of ALS using fluorescent calcium imaging. When comparing vulnerable motor neurons and non-motor neurons from G93A hSOD1 mice and their non-transgenic littermates, we found a decelerated cytosolic calcium clearance in the presence of G93A hSOD1. While both non-transgenic as well as G93A hSOD1 motor neurons displayed large mitochondrial calcium uptake by the mitochondrial uniporter (mUP), the mitochondrial calcium extrusion system was altered in the presence of G93A hSOD1. In addition, ER calcium uptake by the sarco-/endoplasmic reticulum ATPase (SERCA) was increased in G93A hSOD1 motor neurons. In survival assays, blocking the mitochondrial sodium calcium exchanger (mNCE) by CGP37157 as well as inhibiting SERCA by cyclopiazonic acid showed protective effects against kainate induced excitotoxicity. Thus, our study shows for the first time that the functional consequence of G93A hSOD1 overexpression in intact motor neurons is indeed a disturbance of the ER mitochondria calcium cycle, and identified two promising targets for therapeutic intervention in the pathology of ALS. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/23578819/Overexpression_of_human_mutated_G93A_SOD1_changes_dynamics_of_the_ER_mitochondria_calcium_cycle_specifically_in_mouse_embryonic_motor_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(13)00121-0 DB - PRIME DP - Unbound Medicine ER -