From clues to mechanisms - Understanding ALS initiation and spread

Baystate Medical Center/Tufts University School of Medicine, 759 Chestnut Street, S4648, Springfield, MA 01199 .
Neurology (Impact Factor: 8.29). 10/2008; 71(12):872-3. DOI: 10.1212/01.wnl.0000325992.50108.60
Source: PubMed
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    • "The SOD1G93A mouse, for example, shows evidence of a concurrent reduction of midbrain dopaminergic neurons in the substantia nigra (26%) and in the ventral tegmental area (16%), when up to 50% of MNs of the spinal cord are lost (Kostic et al., 1997). Thus, despite the considerable progress in disclosing the multiple molecular processes involved in the ALS pathology, relatively little is known about when and how the disease spreads throughout the motor network (Armon, 2008). In this context cortical hyperexcitability seems to be a phenomenon specific to ALS rather than a general feature of degenerative MN disorders (Vucic, 2009a). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders. The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function.
    Full-text · Article · Nov 2015 · Neuroscience & Biobehavioral Reviews
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    • "Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease defined by the degeneration of both upper and lower motor neurons in the brain and spinal cord. ALS is often subtyped into several variants based on the site of onset (e.g., bulbar, spinal, and respiratory [1]). Bulbar ALS, which affects speech and swallowing, is characterized by the eventual loss of speech intelligibility and ability to swallow [2– 4]. "
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    ABSTRACT: Purpose: To develop a predictive model of speech loss in persons with amyotrophic lateral sclerosis (ALS) based on measures of respiratory, phonatory, articulatory, and resonatory functions that were selected using a data-mining approach. Method: Physiologic speech subsystem (respiratory, phonatory, articulatory, and resonatory) functions were evaluated longitudinally in 66 individuals with ALS using multiple instrumentation approaches including acoustic, aerodynamic, nasometeric, and kinematic. The instrumental measures of the subsystem functions were subjected to a principal component analysis and linear mixed effects models to derive a set of comprehensive predictors of bulbar dysfunction. These subsystem predictors were subjected to a Kaplan-Meier analysis to estimate the time until speech loss. Results: For a majority of participants, speech subsystem decline was detectible prior to declines in speech intelligibility and speaking rate. Among all subsystems, the articulatory and phonatory predictors were most responsive to early bulbar deterioration; and the resonatory and respiratory predictors were as responsive to bulbar decline as was speaking rate. Conclusions: The articulatory and phonatory predictors are sensitive indicators of early bulbar decline due to ALS, which has implications for predicting disease onset and progression and clinical management of ALS.
    Full-text · Article · Jul 2015 · Behavioural neurology
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    • "Despite progress in revealing multiple molecular processes involved in disease pathology, relatively little is known about when and how the disekease, which starts focally, spreads throughout the motor network.10–12 Interestingly, even in the subtypes of ALS caused by SOD1 mutations, there is considerable phenotypic heterogeneity. "
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    ABSTRACT: Objective To determine, when, how, and which neurons initiate the onset of pathophysiology in amyotrophic lateral sclerosis (ALS) using a transgenic mutant sod1 zebrafish model and identify neuroprotective drugs. Methods Proteinopathies such as ALS involve mutant proteins that misfold and activate the heat shock stress response (HSR). The HSR is indicative of neuronal stress, and we used a fluorescent hsp70-DsRed reporter in our transgenic zebrafish to track neuronal stress and to measure functional changes in neurons and muscle over the course of the disease. Results We show that mutant sod1 fish first exhibited the HSR in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. The loss of inhibition was followed by increased stress in the motor neurons of symptomatic adults and concurrent morphological changes at the neuromuscular junction (NMJ) indicative of denervation. Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response. Interpretation The earliest event in the pathophysiology of ALS in the mutant sod1 zebrafish model involves neuronal stress in inhibitory interneurons, resulting from mutant Sod1 expression. This is followed by a reduction in inhibitory input to motor neurons. The loss of inhibitory input may contribute to the later development of neuronal stress in motor neurons and concurrent inability to maintain the NMJ. Riluzole, the approved drug for use in ALS, modulates neuronal stress in interneurons, indicating a novel mechanism of riluzole action. ANN NEUROL 2013;73:246–258
    Full-text · Article · Feb 2013 · Annals of Neurology
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