Protein kinetics of superoxide dismutase-1 in familial and sporadic amyotrophic lateral sclerosis

OBJECTIVE: Accumulation of misfolded superoxide dismutase-1 (SOD1) is a pathological hallmark of SOD1-related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. METHODS: We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. RESULTS: In participants with heterozygous SOD1 INTERPRETATION: These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03449212

In vivo kinetic approach reveals slow SOD1 turnover in the CNS

Therapeutic strategies that target disease-associated transcripts are being developed for a variety of neurodegenerative syndromes. Protein levels change as a function of their half-life, a property that critically influences the timing and application of therapeutics. In addition, both protein kinetics and concentration may play important roles in neurodegeneration; therefore, it is essential to understand in vivo protein kinetics, including half-life. Here, we applied a stable isotope-labeling technique in combination with mass spectrometric detection and determined the in vivo kinetics of superoxide dismutase 1 (SOD1), mutation of which causes amyotrophic lateral sclerosis. Application of this method to human SOD1-expressing rats demonstrated that SOD1 is a long-lived protein, with a similar half-life in both the cerebral spinal fluid (CSF) and the CNS. Additionally, in these animals, the half-life of SOD1 was longest in the CNS when compared with other tissues. Evaluation of this method in human subjects demonstrated successful incorporation of the isotope label in the CSF and confirmed that SOD1 is a long-lived protein in the CSF of healthy individuals. Together, the results of this study provide important insight into SOD1 kinetics and support application of this technique to the design and implementation of clinical trials that target long-lived CNS proteins

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability

Defining SOD1 ALS natural history to guide therapeutic clinical trial design

ImportanceUnderstanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.ObjectiveTo establish an updated natural history of ALSSOD1.Design, setting and participantsRetrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.Main outcomes and measuresAge of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.ResultsMean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02).Conclusions and relevanceSOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population

Defining SOD1 ALS natural history to guide therapeutic clinical trial design

IMPORTANCE: Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS(SOD1)) will provide key information for optimising clinical trials in this patient population. OBJECTIVE: To establish an updated natural history of ALS(SOD1). DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. MAIN OUTCOMES AND MEASURES: Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1(A4V)), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1(non-A4V)) for analysis. RESULTS: Mean age of disease onset was 49.7 ±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1(A4V) and SOD1(non-A4V) (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1(A4V). SOD1(A4V) survival probability (median survival 1.2 years) was significantly decreased compared with SOD1(non-A4V) (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1(A4V) compared with SOD1(non-A4V) participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1(A4V) compared with SOD1(non-A4V) (p=0.02). CONCLUSIONS AND RELEVANCE: SOD1(A4V) is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS(SOD1) patient population

Correction to: The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration (Nature Communications, (2022), 13, 1, (6901), 10.1038/s41467-022-34620-y)

Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-022-34620-y, published online 12 November 2022 The original version of this Article contained an error in Figure 4. Under the heading ‘Disease duration (months)’, all disease durations were reported as ‘disease duration’ rather than reporting the numerical value. The correct version now reports the disease duration in months instead of the original, incorrect ‘disease duration’. This has been corrected in both the PDF and HTML versions of the Article. The correct version of Figure 4 is: (Figure presented.) which replaces the previous incorrect version: (Figure presented.

Correction to:The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration (Nature Communications, (2022), 13, 1, (6901), 10.1038/s41467-022-34620-y)

Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-022-34620-y, published online 12 November 2022 The original version of this Article contained an error in Figure 4. Under the heading ‘Disease duration (months)’, all disease durations were reported as ‘disease duration’ rather than reporting the numerical value. The correct version now reports the disease duration in months instead of the original, incorrect ‘disease duration’. This has been corrected in both the PDF and HTML versions of the Article. The correct version of Figure 4 is: (Figure presented.) which replaces the previous incorrect version: (Figure presented.)</p