A natural history comparison of SOD1-mutant patients with amyotrophic lateral sclerosis between Chinese and German populations

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.

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HtrA2/Omi-immunoreactive intraneuronal inclusions in the anterior horn of patients with sporadic and Cu/Zn superoxide dismutase (SOD1) mutant amyotrophic lateral sclerosis

Neuropathology and Applied Neurobiology ◽

10.1111/j.1365-2990.2010.01075.x ◽

2010 ◽

Vol 36 (4) ◽

pp. 331-344 ◽

Cited By ~ 5

Author(s):

Y. Kawamoto ◽

H. Ito ◽

Y. Kobayashi ◽

Y. Suzuki ◽

I. Akiguchi ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Anterior Horn ◽

Sod1 Mutant ◽

Lateral Sclerosis

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

10.21203/rs.3.rs-603164/v2 ◽

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.

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Su2028 – Natural History of Percutaneous Enteral Gastrostomy Tube in Patients with Amyotrophic Lateral Sclerosis

Gastroenterology ◽

10.1016/s0016-5085(19)38660-3 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-695

Author(s):

Mohanad T. Al-Qaisi ◽

Richard Gerkin ◽

Logan Cobb ◽

Mary Chew ◽

Katherine Petersen ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Natural History ◽

Gastrostomy Tube ◽

History Of ◽

Lateral Sclerosis

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Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons

Cells ◽

10.3390/cells10102773 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2773

Author(s):

Hsiao-Chien Ting ◽

Hui-I Yang ◽

Horng-Jyh Harn ◽

Ing-Ming Chiu ◽

Hong-Lin Su ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Nerve Fiber ◽

Motor Neurons ◽

Induced Pluripotent Stem Cell ◽

Therapeutic Effects ◽

Patient Death ◽

Sporadic Als ◽

Sod1 Mutant ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, SOD1G85R mutant and corrected SOD1G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS (SOD1G85R and SOD1D90A), two SOD1 mutant corrected (SOD1G85G and SOD1D90D), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1D90A ALS MNs in a previous study. Moreover, we found that both SOD1 mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of Gastrodia elata, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1G93A ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3β activation on SOD1 ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.

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

Journal of Neurophysiology ◽

10.1152/jn.00482.2009 ◽

2009 ◽

Vol 102 (6) ◽

pp. 3627-3642 ◽

Cited By ~ 67

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.

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