Universität zu Köln

Simons, Carsten, Benkert, Julia, Deuter, Nora, Poetschke, Christina, Pongs, Olaf, Schneider, Toni, Duda, Johanna and Liss, Birgit (2019). NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons. Front. Molec. Neurosci., 12. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1662-5099

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Abstract

Neuronal Ca2+ sensor proteins (NCS) transduce changes in Ca2+ 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 Ca2+ 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 Ca2+-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 Ca2+ channel Cav2.3 in SN DA neurons from NCS-1 KO. Transcripts of other analyzed uncoupling proteins (UCPs), mitochondrial Ca2+ 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 Cav2.3 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 mitochondria! metabolic stress, and in this way could protect SN DA neurons from degeneration.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Simons, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Benkert, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Deuter, Nora UNSPECIFIED UNSPECIFIED UNSPECIFIED Poetschke, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Pongs, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Toni UNSPECIFIED UNSPECIFIED UNSPECIFIED Duda, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Liss, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-126979
DOI:	10.3389/fnmol.2019.00252
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 GATED CALCIUM-CHANNEL; UV-LASER MICRODISSECTION; PARKINSONS-DISEASE; UNCOUPLING PROTEINS; SENSOR PROTEINS; CA2+ SENSOR-1; TRANSCRIPTION; EXPRESSION; RECEPTOR; DREAM Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12697