Key points• So far, increased excitability and calcium handling problems have been discussed as causes for motoneuron death in amyotrophic lateral sclerosis (ALS) mainly on the basis of studies in juvenile presymptomatic mice.• We developed a brainstem preparation to analyse excitability and calcium handling during disease progression up to disease endstage of motoneurons in an ALS mouse model. • Increased excitability of motoneurons is not seen at disease endstage, challenging this factor as a direct cause for motoneuron death in ALS.• We show that calcium handling is remodelled during disease progression from mitochondrial uptake to mitochondrial uptake failure and increased plasma membrane extrusion, providing a compensatory mechanism that fails at disease endstage and might lead to a toxic calcium overload of the cells. • Supporting this newly described compensatory endeavour of the motoneurons might be a promising therapeutic strategy.Abstract Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that targets some somatic motoneuron populations, while others, e.g. those of the oculomotor system, are spared. The pathophysiological basis of this pattern of differential vulnerability, which is preserved in a transgenic mouse model of amyotrophic lateral sclerosis (SOD1 G93A ), and the mechanism of neurodegeneration in general are unknown. Hyperexcitability and calcium dysregulation have been proposed by others on the basis of data from juvenile mice that are, however, asymptomatic. No studies have been done with symptomatic mice following disease progression to the disease endstage. Here, we developed a new brainstem slice preparation for whole-cell patch-clamp recordings and single cell fura-2 calcium imaging to study motoneurons in adult wild-type and SOD1 G93A mice up to disease endstage. We analysed disease-stage-dependent electrophysiological properties and intracellular Ca 2+ handling of vulnerable hypoglossal motoneurons in comparison to resistant oculomotor neurons. Thereby, we identified a transient hyperexcitability in presymptomatic but not in endstage vulnerable motoneurons. Additionally, we revealed a remodelling of intracellular Ca 2+ clearance within vulnerable but not resistant motoneurons at disease endstage characterised by a reduction of uniporter-dependent mitochondrial Ca 2+ uptake and enhanced Ca 2+ extrusion across the plasma membrane. Our study challenged the notion that hyperexcitability is a direct cause
Disturbances in Ca2+ homeostasis and mitochondrial dysfunction have emerged as major pathogenic features in familial and sporadic forms of Amyotrophic Lateral Sclerosis (ALS), a fatal degenerative motor neuron disease. However, the distinct molecular ALS-pathology remains unclear. Recently, an activity-dependent Ca2+ homeostasis deficit, selectively in highly vulnerable cholinergic motor neurons in the hypoglossal nucleus (hMNs) from a common ALS mouse model, the endstage superoxide dismutase SOD1G93A transgenic mouse, was described. This functional deficit was defined by a reduced hMN mitochondrial Ca2+ uptake capacity and elevated Ca2+ extrusion across the plasma membrane. To address the underlying molecular mechanisms, here we quantified mRNA-levels of respective potential mitochondrial and plasma membrane Ca2+ transporters in individual, choline-acetyltransferase (ChAT) positive hMNs from wildtype (WT) and endstage SOD1G93A mice, by combining UV laser microdissection with RT-qPCR techniques, and specific data normalization. As ChAT cDNA levels as well as cDNA and genomic DNA levels of the mitochondrially encoded NADH dehydrogenase ND1 were not different between hMNs from WT and endstage SOD1G93A mice, these genes were used to normalize hMN-specific mRNA-levels of plasma membrane and mitochondrial Ca2+ transporters, respectively. We detected about 2-fold higher levels of the mitochondrial Ca2+ transporters MCU/MICU1, Letm1, and UCP2 in remaining hMNs from endstage SOD1G93A mice. These higher expression-levels of mitochondrial Ca2+ transporters in individual hMNs were not associated with a respective increase in number of mitochondrial genomes, as evident from hMN specific ND1 DNA quantification. Normalized mRNA-levels for the plasma membrane Na+/Ca2+ exchanger NCX1 were also about 2-fold higher in hMNs from SOD1G93A mice. Thus, pharmacological stimulation of Ca2+ transporters in highly vulnerable hMNs might offer a neuroprotective strategy for ALS.
Olfactory testing serves as a screening tool for HE and may facilitate grading of HE-severity.
Zusammenfassung Einleitung Systematische Untersuchungen zum objektiven Verständnis von Patienten bezüglich häufiger medizinischer Begriffe in Deutschland sind selten. Methodik 196 Patienten (38 % weiblich, 62 % männlich) in stationären Fachabteilungen an einem kommunalen Krankenhaus wurden mittels eines zuvor entwickelten Fragebogens untersucht. Dieser enthielt 43 Fragen zu häufig im Alltag vorkommenden medizinischen Fachbegriffen. Untersucht wurden der subjektive und objektive Bekanntheitsgrad. Zusätzlich wurde eine Assoziation mit verschiedenen potenziellen Einflussfaktoren (u. a. Ausbildung, Versicherungsstatus, Konsum bestimmter Informationsmedien) durchgeführt. Ergebnisse Durchgehend gaben mehr Patienten an, die Bedeutung medizinischer Begriffe zu kennen, als dies bei objektiver Überprüfung der Fall war. Die Assoziation des medizinischen Kenntnisstandes mit verschiedenen Einflussfaktoren ergab, dass Frauen häufiger über korrektes medizinisches Wissen verfügten als Männer (51,1 vs. 47,2 %, p = 0,12). Das Lebensalter war negativ mit dem medizinischen Kenntnisstand korreliert (p < 0,001). Die Länge der Schulbildung war mit einem besseren medizinischen Kenntnisstand assoziiert (p < 0,001). Privat versicherte Patienten waren besser medizinisch gebildet als gesetzlich Versicherte (p = 0,001). Männliche Patienten mit eher mentaler Arbeit hatten einen besseren Kenntnisstand als solche mit körperlicher Arbeit (51,1 vs. 41,8 %; p = 0,002). Zeitungs- und Fernsehkonsum sowie Anzahl der Arztkontakte waren nicht mit einer Verbesserung des medizinischen Kenntnisstandes vergesellschaftet. Fazit Ein hoher Bekanntheitsgrad medizinischer Begriffe kann Ärzte im Anamnesegespräch dazu verleiten, das Verständnis dieser Begriffe auch von Seiten des Patienten stillschweigend vorauszusetzen. Ärzte sollten daher durch aktives Nachfragen das Verständnis beim Patienten sicherstellen. Zukünftige Erhebungen zur Gesundheitskompetenz auf Patientenseite sollten diese Divergenz zwischen subjektiver Einschätzung und objektivem Wissen berücksichtigen.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.