Emerging mechanisms of molecular pathology in ALS

Peters, Owen M.; Ghasemi, Mehdi; Brown, Robert H.

doi:10.1172/jci71601

Cited by 238 publications

(143 citation statements)

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“…Additional mechanisms might be prooxidant and mitochondrial damage, particularly for species such as Se-IV, Se-VI, and Se-Met [26,34,35,36], copper/zinc superoxide-dismutase translocation into mitochondria, and increased inducible nitric oxide synthase [37], DNA damage [38], and P38-P53 activation [39]; all mechanisms are potentially involved in ALS etiopathogenesis [3,40], and more generally functional alterations due to nonspecific incorporation of selenium species into proteins and to adverse effects on lipid metabolism and protein synthesis [41]. …”

Section: Discussionmentioning

confidence: 99%

“…Mutations linked to protein misfolding (SOD1, FUS, TARDBP, VCP, and C9ORF72), impaired autophagy and degradation systems (TBK1, SQSTM1, VCP, and VAPB), oxidative processes (SOD1 and CHCHD10), transcription factor impairment (FUS and TDP43), intracellular trafficking (OPTN), and alterations affecting the cytoskeleton architecture and dynamics (DCTN1, PRPH, NEFH, PFN1, TUBA4A, and MATR3) have been suggested to be involved in ALS [1,2,3,4]. However, not all carriers of these mutations develop ALS, due to the incomplete penetrance of these mutations, even for that (C9ORF72) which has demonstrated the strongest association with disease risk [5].…”

Section: Introductionmentioning

confidence: 99%

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Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations

Mandrioli¹,

Michalke

Solovyev

et al. 2017

Neurodegener Dis

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Background: Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons. Objective: Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls. Methods: Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls. Results: In a patient with the tubulin-related TUBA4A mutation, we found highly elevated levels (in μg/L) of glutathione-peroxidase-bound selenium (32.8 vs. 1.0) as well as increased levels of selenoprotein-P-bound selenium (2.4 vs. 0.8), selenite (1.8 vs. 0.1), and selenate (0.9 vs. 0.1). In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.38 vs. 0.06). Conclusions: Selenium compounds can impair tubulin synthesis and the cytoskeleton structure, as do tubulin-related gene mutations. The elevated selenium species levels in the TUBA4A patient may have a genetic etiology and/or represent a pathogenic pathway through which this mutation favors disease onset, though unmeasured confounding cannot be excluded. The elevated selenomethionine levels in the other patients are also of interest due to the toxicity of this nonphysiological selenium species. Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations

Mandrioli¹,

Michalke

Solovyev

et al. 2017

Neurodegener Dis

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“…An unquestionable set of genetic evidence indicates that disturbed RNA metabolism is a key player in ALS pathogenesis (106). Indeed, more and more genes with an established or probable role in RNA processing have been discovered as to be causally linked to familial as well as to apparently sporadic forms of the disease.…”

Section: Introductionmentioning

confidence: 99%

Old versus New Mechanisms in the Pathogenesis of ALS

2016

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Amyotrophic Lateral Sclerosis (ALS) is recognized as a very complex disease. As we have learned in the past 20 years from studies in patients and in models based on the expression of mutant SOD1, ALS is not a purely motor neuron disease as previously thought. While undoubtedly motor neurons are lost in patients, a number of alterations in those cell-types that interact functionally with motor neurons (astrocytes, microglia, muscle fibers, oligodendrocytes) take place even long before onset of symptoms. At the same time, disturbance of several, only partly inter-related physiological functions play some role in the onset and progression of the disease. Traditionally, mitochondrial damage and oxidative stress, excitotoxicity, neuroinflammation, altered axonal transport, ER stress, protein aggregation and defective removal of toxic proteins have been considered as key factors in the pathogenesis of ALS, with the relatively recent addition of disturbances in RNA metabolism. This complexity makes the search for an effective treatment extremely difficult and prompts further studies to reveal other possible, previously unappreciated aspects of the pathogenesis of ALS. In this review, we focus on previous knowledge on ALS mechanisms as well as new facets emerging from studies on genetic ALS patients and models that may both provide precious information for a novel therapeutic approach.

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“…To date, more than 20 different genes have been discovered linked to the development of amyotrophic lateral sclerosis (ALS), with C9ORF72, TARDBP, SOD1 and FUS being the most prevalent 1. Since the discovery of the SOD1 mutation in 1993—the first gene associated with the disease—models based on this genetic mutation have made a significant contribution to understanding ALS pathogenesis.…”

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confidence: 99%