Pathogenesis of amyotrophic lateral sclerosis

Morgan, Sarah; Orrell, Richard W.

doi:10.1093/bmb/ldw026

Cited by 137 publications

(87 citation statements)

References 59 publications

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“…The analysis of DE genes (mRNAs) confirmed the importance of 12 genes (PFN1, TUBA4A, PARK7, SQSTM1, DCTN1, C9orf72, TMEM106B, ALS2, TRPM7, MATR3, SPG11 , and ATXN2) whose mutations have been already identified as causative of sALS/fALS (Renton et al, 2014; Morgan and Orrell, 2016; Al-Chalabi et al, 2017; Brown and Al-Chalabi, 2017; van Es et al, 2017; Zou et al, 2017; Chia et al, 2018). In future analysis we will perform exomes sequencing to check the presence of pathogenic mutations in the genes of recruited patients.…”

Section: Discussionmentioning

confidence: 69%

“…Indeed, several factors other than genes (toxic exposures, diet, and others) seem to possibly contribute to ALS pathogenesis (Paez-Colasante et al, 2015; Morgan and Orrell, 2016; Al-Chalabi et al, 2017) but a definitive conclusion on the effective role of the different factors is still awaited, mostly due to methodological biases (i.e., low power of the studies) (van Es et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

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Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis

Liguori

Nuzziello

Introna

et al. 2018

Front. Mol. Neurosci.

110

106

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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease. While genetics and other factors contribute to ALS pathogenesis, critical knowledge is still missing and validated biomarkers for monitoring the disease activity have not yet been identified. To address those aspects we carried out this study with the primary aim of identifying possible miRNAs/mRNAs dysregulation associated with the sporadic form of the disease (sALS). Additionally, we explored miRNAs as modulating factors of the observed clinical features. Study included 56 sALS and 20 healthy controls (HCs). We analyzed the peripheral blood samples of sALS patients and HCs with a high-throughput next-generation sequencing followed by an integrated bioinformatics/biostatistics analysis. Results showed that 38 miRNAs (let-7a-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-103a-3p, miR-106b-3p, miR-128-3p, miR-130a-3p, miR-130b-3p, miR-144-5p, miR-148a-3p, miR-148b-3p, miR-15a-5p, miR-15b-5p, miR-151a-5p, miR-151b, miR-16-5p, miR-182-5p, miR-183-5p, miR-186-5p, miR-22-3p, miR-221-3p, miR-223-3p, miR-23a-3p, miR-26a-5p, miR-26b-5p, miR-27b-3p, miR-28-3p, miR-30b-5p, miR-30c-5p, miR-342-3p, miR-425-5p, miR-451a, miR-532-5p, miR-550a-3p, miR-584-5p, miR-93-5p) were significantly downregulated in sALS. We also found that different miRNAs profiles characterized the bulbar/spinal onset and the progression rate. This observation supports the hypothesis that miRNAs may impact the phenotypic expression of the disease. Genes known to be associated with ALS (e.g., PARK7, C9orf72, ALS2, MATR3, SPG11, ATXN2) were confirmed to be dysregulated in our study. We also identified other potential candidate genes like LGALS3 (implicated in neuroinflammation) and PRKCD (activated in mitochondrial-induced apoptosis). Some of the downregulated genes are involved in molecular bindings to ions (i.e., metals, zinc, magnesium) and in ions-related functions. The genes that we found upregulated were involved in the immune response, oxidation–reduction, and apoptosis. These findings may have important implication for the monitoring, e.g., of sALS progression and therefore represent a significant advance in the elucidation of the disease’s underlying molecular mechanisms. The extensive multidisciplinary approach we applied in this study was critically important for its success, especially in complex disorders such as sALS, wherein access to genetic background is a major limitation.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis

Liguori

Nuzziello

Introna

et al. 2018

Front. Mol. Neurosci.

110

106

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“…Mutations identified in familial forms (<10% cases) have been also reported in less than 10% sporadic forms (Millecamps et al 2012). Several putative aetiological factors have been proposed, including oxidative stress, intracellular protein aggregation, mitochondrial dysfunction, impaired axonal transport, inflammation and glutamate excitotoxicity, although the unifying pathogenesis of ALS remains notoriously elusive (Rothstein, 2009;Morgan & Orrell, 2016).…”

Section: Introductionmentioning

confidence: 99%

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Marchand‐Pauvert

Peyre

Lackmy-Vallée

et al. 2019

The Journal of Physiology

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Key points •Amyotrophic lateral sclerosis (ALS) motoneurons become hypoexcitable with disease progression in experimental models, raising questions about the neural hyperexcitability supported by clinical observations. •A variant of the ∆F method, based on motor unit discharge frequency modulations during recruitment and derecruitment, has been developed to investigate the motoneuron capacity to self‐sustained discharge in patients. •The modulation of motor unit firing rate during ramp contraction and vibration‐induced recruitment are modified in ALS, suggesting lower motoneuron capacity to self‐sustained discharge, which is a sign of hypoexcitability. •∆F‐D decreases with functional impairment and its reduction is more pronounced in fast progressors. •In patients with ALS, motoneurons exhibit hypoexcitability, which increases with disease progression. Abstract Experimental models have primarily revealed spinal motoneuron hypoexcitability in amyotrophic lateral sclerosis (ALS), which is contentious considering the role of glutamate‐induced excitotoxicity in neurodegeneration and clinical features rather supporting hyperexcitability. This phenomenon was evaluated in human patients by investigating changes in motor unit firing during contraction and relaxation. Twenty‐two ALS patients with subtle motor deficits and 28 controls performed tonic contractions of extensor carpi radialis, triceps brachialis, tibialis anterior and quadriceps, aiming to isolate a low‐threshold unit (U1) on the electromyogram (EMG). Subsequently, they performed a stronger contraction or tendon vibration was delivered, to recruit higher threshold unit (U2) for 10 s before they relaxed progressively. EMG and motor unit potential analyses suggest altered neuromuscular function in all muscles, including those with normal strength (Medical Research Council score at 5). During the preconditioning tonic phase, U1 discharge frequency did not differ significantly between groups. During recruitment, the increase in U1 frequency (∆F‐R) was comparable between groups both during contraction and tendon vibration. During derecruitment, the decrease in U1 frequency (∆F‐D) was reduced in ALS regardless of the recruitment mode, particularly for ∆F‐R <8 Hz in the upper limbs, consistent with the muscle weakness profile of the group. ∆F‐D was associated with functional disability and its reduction was more pronounced in patients with more rapid disease progression rate. This in vivo study has demonstrated reduced motoneuron capacity for self‐sustained discharge, and further supports that motoneurons are normo‐ to hypoexcitable in ALS patients, similar to observations in experimental models.

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“…The complexity of the molecular mechanisms implicated in ALS is paralleled by multifaceted genetics that are still not fully understood despite extensive research (Al-Chalabi and Hardiman, 2013; Morgan and Orrell, 2016). To address this issue, there has been a move towards next-generation sequencing (NGS) as a high-throughput, relatively inexpensive tool to uncover the genetic architecture of ALS and other heterogeneous neurological diseases, including Charcot–Marie–Tooth disease, dementia, ataxia and Parkinson’s disease (Johnson et al , 2010; Mencacci et al , 2014; Cady et al , 2015; Cirulli et al , 2015; van Rheenen et al , 2016).…”

Section: Introductionmentioning

confidence: 99%

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK

Morgan

Shatunov

Sproviero

et al. 2017

Brain

Self Cite

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Pathogenesis of amyotrophic lateral sclerosis

Cited by 137 publications

References 59 publications

Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis

Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK

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