Early Excitability Changes in Lumbar Motoneurons of Transgenic SOD1G85R and SOD1G93A-Low Mice

2009 ◽  
Vol 102 (6) ◽  
pp. 3627-3642 ◽  
Author(s):  
Arnaud Pambo-Pambo ◽  
Jacques Durand ◽  
Jean-Patrick Gueritaud
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Wild Type ◽  
Persistent Inward Currents ◽  
Current Pulses ◽  
Inward Currents ◽  
Recording Conditions ◽  
Mutant Lines ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

This work characterizes the properties of wild-type (WT) mouse motoneurons in the second postnatal week and compares these at the same age and in the same conditions to those of two different SOD1 mutant lines used as models of human amyotrophic lateral sclerosis (ALS), the SOD1G93A low expressor line and SOD1G85R line, to describe any changes in the functional properties of mutant motoneurons (Mns) that may be related to the pathogenesis of human ALS. We show that very early changes in excitability occur in SOD1 mutant Mns that have different properties from those of WT animals. The SOD1G93A-Low low expressor line displays specific differences that are not found in other mutant lines including a more depolarized membrane potential, larger spike width, and slower spike rise slope. With current pulses SOD1G93A-Low were hyperexcitable, but both mutants had a lower gain with current ramps stimulation. Changes in the threshold and intensities of Na+ and Ca2+ persistent inward currents were also observed. Low expressor mutants show reduced total persistant inward currents compared with WT motoneurons in the same recording conditions and give arguments toward modifications of the balance between Na+ and Ca2+ persistent inward currents. During the second week postnatal, SOD1G93A-Low lumbar motoneurons appear more immature than those of SOD1G85R compared with WT and we propose that different time course of the disease, possibly linked with different toxic properties of the mutated protein in each model, may explain the discrepancies between excitability changes described in the different models.

scholarly journals Spinal motoneurones are intrinsically more responsive in the adult G93A SOD1 mouse model of Amyotrophic Lateral Sclerosis

2020 ◽  
Author(s):  
D.B. Jensen ◽  
M. Kadlecova ◽  
I. Allodi ◽  
C.F. Meehan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Repetitive Firing ◽  
Intracellular Recordings ◽  
Persistent Inward Currents ◽  
Inward Currents ◽  
Spinal Motoneurones ◽  
Sod1 Mouse ◽  
G93a Sod1 ◽  
Lateral Sclerosis

AbstractIn vitro studies from transgenic Amyotrophic Lateral Sclerosis models have suggested an increased excitability of spinal motoneurones. However, in vivo intracellular recordings from adult ALS mice models have produced conflicting findings. Previous publications using barbiturate anaesthetised G93A SOD1 mice suggested that some motoneurones are hypo-excitable, defined by deficits in repetitive firing. Our own previous recordings in G127X SOD1 mice using different anaesthesia, however, showed no repetitive firing deficits, and increased persistent inward currents at symptom onset. These discrepancies may be due to differences between models, symptomatic stage, anaesthesia or technical differences. To investigate this, we repeated our original experiments, but in adult male G93A mice at both presymptomatic and symptomatic stages, under barbiturate anaesthesia.In vivo intracellular recordings from antidromically identified spinal motoneurones revealed no significant differences in the ability to fire repetitively in the G93A SOD1 mice. Motoneurones in G93A SOD1 mice fired significantly more spontaneous action potentials. Rheobase was significantly lower and the input resistance and input-output gain were significantly higher in both presymptomatic and symptomatic G93A SOD1 mice. This was despite a significant increase in the duration of the post-spike after-hyperpolarisation (AHP) in both presymptomatic and symptomatic G93A SOD1 mice. Finally, evidence of increased activation of persistent inward currents was seen in both presymptomatic and symptomatic G93A SOD1 mice. Our results do not confirm previous reports of hypo-excitability of spinal motoneurones in the G93A SOD1 mouse and demonstrate that the motoneurones do in fact show an increased response to inputs.Key Point SummaryAlthough in vitro recordings using neonatal preparations from mouse models of Amyotrophic Lateral Sclerosis (ALS) suggest increased motoneurone excitability, in vivo recordings in adult ALS mouse models have been conflicting.In adult G93A SOD1 models, spinal motoneurones have previously been shown to have deficits in repetitive firing, in contrast to the G127X SOD1 mouse model.Our in vivo intracellular recordings in barbiturate-anaesthetised adult male G93A SOD1 mice reveal no deficits in repetitive firing either prior to or after symptom onset.We show that deficits in repetitive firing ability can be a consequence of experimental protocol and should not be used alone to classify otherwise normal motoneurones as hypo-excitable.Motoneurones in the G93A SOD1 mice showed an increased response to inputs, with lower rheobase, higher input-output gains and increased activation of persistent inward currents.

scholarly journals Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

2021 ◽  
Author(s):  
Fabiola De Marchi ◽  
◽  
Claudia Carrarini ◽  
Antonio De Martino ◽  
Luca Diamanti ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Multisystem Disorder ◽  
Behavioral Impairment ◽  
Behavioral Impairments ◽  
Als Patients ◽  
Disease Stages ◽  
Lateral Sclerosis

Abstract Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

Computational investigation of the human SOD1 mutant, Cys146Arg, that directs familial amyotrophic lateral sclerosis

2017 ◽  
Vol 13 (8) ◽  
pp. 1495-1503 ◽  
Author(s):  
E. Srinivasan ◽  
R. Rajasekaran
Keyword(s):  
Molecular Dynamics ◽  
Amyotrophic Lateral Sclerosis ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Computational Investigation ◽  
Conformational Preferences ◽  
Dynamics Simulations ◽  
Sod1 Mutant ◽  
Human Sod1 ◽  
Lateral Sclerosis ◽  
Computational Predictions

Molecular dynamics simulations along with the computational predictions used to assess the protein structural characterization as well as the conformational preferences of the monomeric native and mutant SOD1.

scholarly journals A Natural History Comparison of SOD1-Mutant Patients with Amyotrophic Lateral Sclerosis between Chinese and German Populations

2021 ◽  
Author(s):  
Lu Tang ◽  
Johannes Dorst ◽  
Lu Chen ◽  
Xiaolu Liu ◽  
Yan Ma ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Age Of Onset ◽  
Diagnostic Delay ◽  
Chinese Patients ◽  
Common Mutation ◽  
Progression Rate ◽  
Causative Gene ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

Abstract Background: The gene coding the Cu/Zn superoxide dismutase ( SOD1 ) was the first-identified causative gene of amyotrophic lateral sclerosis (ALS), and the second most common genetic cause for ALS worldwide. The promising therapeutic approaches targeting SOD1 mutations are on the road. The purpose of the present study was to compare the mutational and clinical features of Chinese and German patients with ALS carrying mutations in SOD1 gene, which will facilitate the strategy and design of SOD1 -targeted trials.Methods: Demographic and clinical characteristics were collected from two longitudinal cohorts in China and Germany. Chinese and German patients carrying SOD1 mutations were compared with regard to mutational distribution, age of onset, site of onset, body mass index (BMI) at diagnosis, diagnostic delay, progression rate, and survival.Results: A total of 66 Chinese and 84 German patients with 69 distinct SOD1 mutations were identified. The most common mutation in both populations was p.His47Arg. It was found in 8 Chinese and 2 German patients and consistently showed a slow progression of disease in both countries. Across all mutations, Chinese patients showed a younger age of onset (43.9 vs 49.9 years, p=0.002), a higher proportion of young-onset cases (62.5% vs 30.7%, p<0.001) and a lower BMI at diagnosis (22.8 vs 26.0, p<0.001) compared to German patients. Although riluzole intake was less frequent in Chinese patients (28.3% vs 81.3%, p<0.001), no difference in survival between populations was observed (p=0.90). Across both cohorts, female patients had a longer diagnostic delay (15.0 vs 11.0 months, p=0.01) and a prolonged survival (248.0 vs 60.0 months, p=0.005) compared to male patients.Conclusions: Our data demonstrate the distinct mutational and clinical spectrums of SOD1 -mutant patients in Asian and European populations. Clinical phenotypes seem to be primarily influenced by mutation-specific, albeit not excluding ethnicity-specific factors. Further large-scale transethnical studies are needed to clarify determinants and modifiers of SOD1 phenotypes.

scholarly journals The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1791
Author(s):  
Ana Bajc Česnik ◽  
Helena Motaln ◽  
Boris Rogelj
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rna Binding ◽  
Neurodegenerative Disorder ◽  
Low Complexity ◽  
Wild Type ◽  
Disease Heterogeneity ◽  
Cytoplasmic Inclusions ◽  
The Impact ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder, characterized by cytoplasmic inclusions of RNA-binding protein TDP-43. Despite decades of research and identification of more than 50 genes associated with amyotrophic lateral sclerosis (ALS), the cause of TDP-43 translocation from the nucleus and its aggregation in the cytoplasm still remains unknown. Our study addressed the impact of selected ALS-associated genes on TDP-43 aggregation behavior in wild-type and aggregation prone TDP-43 in vitro cell models. These were developed by deleting TDP-43 nuclear localization signal and stepwise shortening its low-complexity region. The SH-SY5Y cells were co-transfected with the constructs of aggregation-prone TDP-43 and wild-type or mutant ALS-associated genes hnRNPA1, MATR3, VCP or UBQLN2. The investigated genes displayed a unique impact on TDP-43 aggregation, generating distinct types of cytoplasmic inclusions, similar to those already described as resembling prion strains, which could represent the basis for neurodegenerative disease heterogeneity.

scholarly journals Fully Metallated S134N Cu,Zn-Superoxide Dismutase Displays Abnormal Mobility and Intermolecular Contacts in Solution

2005 ◽  
Vol 280 (43) ◽  
pp. 35815-35821 ◽  
Author(s):  
Lucia Banci ◽  
Ivano Bertini ◽  
Nicola D'Amelio ◽  
Elena Gaggelli ◽  
Elisa Libralesso ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Wild Type ◽  
Mutant Sod1 ◽  
Copper Zinc Superoxide Dismutase ◽  
Intermolecular Contacts ◽  
Nmr Methods ◽  
The Individual ◽  
Lateral Sclerosis

S134N copper-zinc superoxide dismutase (SOD1) is one of the many mutant SOD1 proteins known to cause familial amyotrophic lateral sclerosis. Earlier studies demonstrated that partially metal-deficient S134N SOD1 crystallized in filament-like arrays with abnormal contacts between the individual protein molecules. Because protein aggregation is implicated in SOD1-linked familial amyotrophic lateral sclerosis, abnormal intermolecular interactions between mutant SOD1 proteins could be relevant to the mechanism of pathogenesis in the disease. We have therefore applied NMR methods to ascertain whether abnormal contacts also form between S134N SOD1 molecules in solution and whether Cys-6 or Cys-111 plays any role in the aggregation. Our studies demonstrate that the behavior of fully metallated S134N SOD1 is dramatically different from that of fully metallated wild type SOD1 with a region of subnanosecond mobility located close to the site of the mutation. Such a high degree of mobility is usually seen only in the apo form of wild type SOD1, because binding of zinc to the zinc site normally immobilizes that region. In addition, concentration-dependent chemical shift differences were observed for S134N SOD1 that were not observed for wild type SOD1, indicative of abnormal intermolecular contacts in solution. We have here also established that the two free cysteines (6 and 111) do not play a role in this behavior.

Sign in / Sign up

Export Citation Format

Share Document