Amyotrophic Lateral Sclerosis

Rowland, Lewis P.; Shneider, Neil A.

doi:10.1056/nejm200105313442207

Cited by 1,670 publications

(1,106 citation statements)

References 141 publications

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“…Amyotrophic lateral sclerosis (ALS) is a fatal disease involving progressive motor neuron degeneration 1. The complex pathogenesis and limited efficacy of disease‐modifying therapies predicates an urgent need for novel treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Goutman

Brown

Glass

et al. 2018

Ann Clin Transl Neurol

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ObjectiveIntraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs.MethodsSurvival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20.ResultsSurvival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study.InterpretationComparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study.

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Section: Introductionmentioning

confidence: 99%

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Goutman

Brown

Glass

et al. 2018

Ann Clin Transl Neurol

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“…Amyotrophic lateral sclerosis (ALS) 1 is a heterogeneous neurological disorder characterized by progressive degeneration of motor neurons, usually causing death as a result of respiratory paralysis (1,2). Although mostly sporadic in nature, a genetic link has been established in 5-10% of ALS cases (3).…”

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confidence: 99%

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Topp

Gray

Gerard

et al. 2004

Journal of Biological Chemistry

173

157

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ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs. To gain insight into the overall function of alsin and to begin to evaluate its role in motor neuron maintenance, we examined the subcellular localization of alsin and the biochemical activities associated with its individual subdomains. We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange activity. In addition, alsin interacted specifically with and acted as a guanine nucleotide exchange factor for Rac1. Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures. Many of these membrane structures also contained Rab5 or Rac1. Upon overexpression of full-length alsin, the overexpressed material was largely cytosolic, indicating that the association with membrane structures could be saturated. We also found that alsin was present in membrane ruffles and lamellipodia. These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.Amyotrophic lateral sclerosis (ALS) 1 is a heterogeneous neurological disorder characterized by progressive degeneration of motor neurons, usually causing death as a result of respiratory paralysis (1, 2). Although mostly sporadic in nature, a genetic link has been established in 5-10% of ALS cases (3). Chromosomal mapping studies have identified six independent loci associated with the familial forms of ALS (Refs. 4 -10; reviewed in Refs. 11 and 12). Molecular genetic analysis identified two genes that, when mutated, lead to ALS. The first discovered was the gene coding for Cu-Zn superoxide dismutase 1 (SOD1) (10). Initially, mutations in SOD1 were thought to result in defective free radical scavenger activity. However, it is now generally accepted that the alterations in SOD1 that lead to ALS are the result of an unknown, but toxic gain-of-function. The second gene identified is mutated in a juvenile form of ALS, ALS2 (13,14). Mutations in this gene lead to a rare recessive form of ALS that presents early in life and progresses much more slowly than the classical form (6, 15). Two small deletions in ALS2 were originally associated with the disease (13,14). Each is expected to severely truncate the predicted protein product of ALS2. In addition, mutations in ALS2 have recently been associated with two other neurodegenerative disorders, juvenile-onset primary lateral sclerosis (14) and infantile-onset hereditary spastic paralegia (16 -18). Like the original mutations identified, these mutations are predicted to generate prematurely truncated forms of the protein product.The protein encoded by ALS2, alsin, is predicted to contain numerous domains implicating roles in cell signaling, membrane localization, and protein...

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“…Amyotrophic lateral sclerosis (ALS) 1 is an age-dependent degenerative disorder of motor neurons in the spinal cord, brain stem, and brain (1). Approximately 10% of ALS cases are familial, and ϳ20% of these individuals inherit one of Ͼ90 autosomal dominant mutations in the gene encoding copper/ zinc superoxide dismutase 1 (SOD1) (2).…”

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confidence: 99%

Familial Amyotrophic Lateral Sclerosis Mutants of Copper/Zinc Superoxide Dismutase Are Susceptible to Disulfide Reduction

Tiwari

Hayward

2003

Journal of Biological Chemistry

198

192

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We observed that 14 biologically metallated mutants of copper/zinc superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis all exhibited aberrantly accelerated mobility during partially denaturing PAGE and increased sensitivity to proteolytic digestion compared with wild type SOD1. Decreased metal binding site occupancy and exposure to the disulfide-reducing agents dithiothreitol, Tris(2-carboxyethyl)phosphine (TCEP), or reduced glutathione increased the fraction of anomalously migrating mutant SOD1 proteins. Furthermore, the incubation of mutant SOD1s with TCEP increased the accessibility to iodoacetamide of cysteine residues that normally participate in the formation of the intrasubunit disulfide bond (Cys-57 to Cys-146) or are buried within the core of the ␤-barrel (Cys-6). SOD1 enzymes in spinal cord lysates from G85R and G93A mutant but not wild type SOD1 transgenic mice also exhibited abnormal vulnerability to TCEP, which exposed normally inaccessible cysteine residues to modification by maleimide conjugated to polyethylene glycol. These results implicate SOD1 destabilization under cellular disulfide-reducing conditions at physiological pH and temperature as a shared property that may be relevant to amyotrophic lateral sclerosis mutant neurotoxicity.Amyotrophic lateral sclerosis (ALS) 1 is an age-dependent degenerative disorder of motor neurons in the spinal cord, brain stem, and brain (1). Approximately 10% of ALS cases are familial, and ϳ20% of these individuals inherit one of Ͼ90 autosomal dominant mutations in the gene encoding copper/ zinc superoxide dismutase 1 (SOD1) (2). 2 SOD1 is a 32-kDa homodimeric enzyme expressed predominantly in the cytosol that decreases the intracellular concentration of superoxide radicals (O 2 . ) by catalyzing their dismutation to O 2 and H 2 O 2 . ALS-associated mutations of conserved residues throughout the protein impart a toxic property to the enzyme that appears unrelated to its normal dismutase activity (reviewed in Ref.3). Whereas transgenic mice that overexpress mutant SOD1s consistently develop lethal motor neuron degeneration (4 -8), mice that overexpress the wild type (WT) enzyme exhibit only subtle motor abnormalities (9). In addition, SOD1 knock-out mice are not susceptible to motor neuron loss unless following axonal injury (10). Mutant SOD1 enzymes have been proposed to facilitate aberrant copper-mediated chemistry, disrupt protein recycling or chaperone function, form toxic aggregates, or induce organelle dysfunction or apoptosis (3,11,12), but the precise mechanism of specific motor neuron toxicity has not been elucidated. The observation that some mutant SOD1s exhibit accelerated turnover in vivo or increased proteolytic susceptibility compared with the WT enzyme (13-15) suggests that biologically significant perturbations of mutant SOD1 conformation occur. The induction of chaperone proteins that can protect cultured motor neurons from mutant SOD1 toxicity (16) and appear to associate with SOD1 mutants (17) provides further...

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Amyotrophic Lateral Sclerosis

Cited by 1,670 publications

References 141 publications

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Familial Amyotrophic Lateral Sclerosis Mutants of Copper/Zinc Superoxide Dismutase Are Susceptible to Disulfide Reduction

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