Cargando…

NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons

Neuronal Ca(2+) sensor proteins (NCS) transduce changes in Ca(2+) homeostasis into altered signaling and neuronal function. NCS-1 activity has emerged as important for neuronal viability and pathophysiology. The progressive degeneration of dopaminergic (DA) neurons, particularly within the Substanti...

Descripción completa

Detalles Bibliográficos
Autores principales: Simons, Carsten, Benkert, Julia, Deuter, Nora, Poetschke, Christina, Pongs, Olaf, Schneider, Toni, Duda, Johanna, Liss, Birgit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890851/
https://www.ncbi.nlm.nih.gov/pubmed/31827421
http://dx.doi.org/10.3389/fnmol.2019.00252
_version_ 1783475702248505344
author Simons, Carsten
Benkert, Julia
Deuter, Nora
Poetschke, Christina
Pongs, Olaf
Schneider, Toni
Duda, Johanna
Liss, Birgit
author_facet Simons, Carsten
Benkert, Julia
Deuter, Nora
Poetschke, Christina
Pongs, Olaf
Schneider, Toni
Duda, Johanna
Liss, Birgit
author_sort Simons, Carsten
collection PubMed
description Neuronal Ca(2+) sensor proteins (NCS) transduce changes in Ca(2+) homeostasis into altered signaling and neuronal function. NCS-1 activity has emerged as important for neuronal viability and pathophysiology. The progressive degeneration of dopaminergic (DA) neurons, particularly within the Substantia nigra (SN), is the hallmark of Parkinson’s disease (PD), causing its motor symptoms. The activity-related Ca(2+) homeostasis of SN DA neurons, mitochondrial dysfunction, and metabolic stress promote neurodegeneration and PD. In contrast, NCS-1 in general has neuroprotective effects. The underlying mechanisms are unclear. We analyzed transcriptional changes in SN DA neurons upon NCS-1 loss by combining UV-laser microdissection and RT-qPCR-approaches to compare expression levels of a panel of PD and/or Ca(2+)-stress related genes from wildtype and NCS-1 KO mice. In NCS-1 KO, we detected significantly lower mRNA levels of mitochondrially coded ND1, a subunit of the respiratory chain, and of the neuron-specific enolase ENO2, a glycolytic enzyme. We also detected lower levels of the mitochondrial uncoupling proteins UCP4 and UCP5, the PARK7 gene product DJ-1, and the voltage-gated Ca(2+) channel Cav2.3 in SN DA neurons from NCS-1 KO. Transcripts of other analyzed uncoupling proteins (UCPs), mitochondrial Ca(2+) transporters, PARK genes, and ion channels were not altered. As Cav channels are linked to regulation of gene expression, metabolic stress and degeneration of SN DA neurons in PD, we analyzed Cav2.3 KO mice, to address if the transcriptional changes in NCS-1 KO were also present in Cav.2.3 KO, and thus probably correlated with lower Cav2.3 transcripts. However, in SN DA neurons from Cav2.3 KO mice, ND1 mRNA as well as genomic DNA levels were elevated, while ENO2, UCP4, UCP5, and DJ-1 transcript levels were not altered. In conclusion, our data indicate a possible novel function of NCS-1 in regulating gene transcription or stabilization of mRNAs in SN DA neurons. Although we do not provide functional data, our findings at the transcript level could point to impaired ATP production (lower ND1 and ENO2) and elevated metabolic stress (lower UCP4, UCP5, and DJ-1 levels) in SN DA neurons from NCS-1 KO mice. We speculate that NCS-1 is involved in stimulating ATP synthesis, while at the same time controlling mitochondrial metabolic stress, and in this way could protect SN DA neurons from degeneration.
format Online
Article
Text
id pubmed-6890851
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-68908512019-12-11 NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons Simons, Carsten Benkert, Julia Deuter, Nora Poetschke, Christina Pongs, Olaf Schneider, Toni Duda, Johanna Liss, Birgit Front Mol Neurosci Neuroscience Neuronal Ca(2+) sensor proteins (NCS) transduce changes in Ca(2+) homeostasis into altered signaling and neuronal function. NCS-1 activity has emerged as important for neuronal viability and pathophysiology. The progressive degeneration of dopaminergic (DA) neurons, particularly within the Substantia nigra (SN), is the hallmark of Parkinson’s disease (PD), causing its motor symptoms. The activity-related Ca(2+) homeostasis of SN DA neurons, mitochondrial dysfunction, and metabolic stress promote neurodegeneration and PD. In contrast, NCS-1 in general has neuroprotective effects. The underlying mechanisms are unclear. We analyzed transcriptional changes in SN DA neurons upon NCS-1 loss by combining UV-laser microdissection and RT-qPCR-approaches to compare expression levels of a panel of PD and/or Ca(2+)-stress related genes from wildtype and NCS-1 KO mice. In NCS-1 KO, we detected significantly lower mRNA levels of mitochondrially coded ND1, a subunit of the respiratory chain, and of the neuron-specific enolase ENO2, a glycolytic enzyme. We also detected lower levels of the mitochondrial uncoupling proteins UCP4 and UCP5, the PARK7 gene product DJ-1, and the voltage-gated Ca(2+) channel Cav2.3 in SN DA neurons from NCS-1 KO. Transcripts of other analyzed uncoupling proteins (UCPs), mitochondrial Ca(2+) transporters, PARK genes, and ion channels were not altered. As Cav channels are linked to regulation of gene expression, metabolic stress and degeneration of SN DA neurons in PD, we analyzed Cav2.3 KO mice, to address if the transcriptional changes in NCS-1 KO were also present in Cav.2.3 KO, and thus probably correlated with lower Cav2.3 transcripts. However, in SN DA neurons from Cav2.3 KO mice, ND1 mRNA as well as genomic DNA levels were elevated, while ENO2, UCP4, UCP5, and DJ-1 transcript levels were not altered. In conclusion, our data indicate a possible novel function of NCS-1 in regulating gene transcription or stabilization of mRNAs in SN DA neurons. Although we do not provide functional data, our findings at the transcript level could point to impaired ATP production (lower ND1 and ENO2) and elevated metabolic stress (lower UCP4, UCP5, and DJ-1 levels) in SN DA neurons from NCS-1 KO mice. We speculate that NCS-1 is involved in stimulating ATP synthesis, while at the same time controlling mitochondrial metabolic stress, and in this way could protect SN DA neurons from degeneration. Frontiers Media S.A. 2019-11-27 /pmc/articles/PMC6890851/ /pubmed/31827421 http://dx.doi.org/10.3389/fnmol.2019.00252 Text en Copyright © 2019 Simons, Benkert, Deuter, Poetschke, Pongs, Schneider, Duda and Liss. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Simons, Carsten
Benkert, Julia
Deuter, Nora
Poetschke, Christina
Pongs, Olaf
Schneider, Toni
Duda, Johanna
Liss, Birgit
NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons
title NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons
title_full NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons
title_fullStr NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons
title_full_unstemmed NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons
title_short NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons
title_sort ncs-1 deficiency affects mrna levels of genes involved in regulation of atp synthesis and mitochondrial stress in highly vulnerable substantia nigra dopaminergic neurons
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890851/
https://www.ncbi.nlm.nih.gov/pubmed/31827421
http://dx.doi.org/10.3389/fnmol.2019.00252
work_keys_str_mv AT simonscarsten ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons
AT benkertjulia ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons
AT deuternora ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons
AT poetschkechristina ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons
AT pongsolaf ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons
AT schneidertoni ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons
AT dudajohanna ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons
AT lissbirgit ncs1deficiencyaffectsmrnalevelsofgenesinvolvedinregulationofatpsynthesisandmitochondrialstressinhighlyvulnerablesubstantianigradopaminergicneurons