Articles: amyotrophic-lateral-sclerosis-pathology.
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Neuroinflammation is a common pathological feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and is characterised by activated CNS microglia and astroglia, proinflammatory peripheral lymphocytes, and macrophages. Data from clinical studies show that multiple genetic mutations linked to ALS (eg, mutations in SOD1, TARDBP, and C9orf72) enhance this neuroinflammation, which provides compelling evidence for immune dysregulation in the pathogenesis of ALS. ⋯ Therefore, an improved understanding of the biological processes that induce this immune dysregulation will help to identify therapeutic strategies that circumvent or ameliorate the pathogenesis of ALS. Emerging cell-based therapies hold the promise of accomplishing this goal and, therefore, improving quality of life and extending survival in patients with ALS.
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J. Neurol. Neurosurg. Psychiatr. · Dec 2018
Regional thalamic MRI as a marker of widespread cortical pathology and progressive frontotemporal involvement in amyotrophic lateral sclerosis.
The thalamus is a major neural hub, with selective connections to virtually all cortical regions of the brain. The multisystem neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) has pathogenic overlap with frontotemporal dementia, and objective in vivo markers of extra-motor pathological spread are lacking. To better consider the role of the thalamus in neurodegeneration, the present study assessed the integrity of the thalamus and its connectivity to major cortical regions of the brain in a longitudinal manner. ⋯ Regional thalamic connectivity changes mirror the progressive frontotemporal cortical involvement associated with the motor functional decline in ALS. Longitudinal MRI thalamic parcellation has potential as a non-invasive surrogate marker of cortical dysfunction in ALS.
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Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to degeneration of motor neurons and skeletal muscles, including those required for swallowing. Tongue weakness is one of the earliest signs of bulbar dysfunction in ALS, which is attributed to degeneration of motor neurons in the hypoglossal nucleus in the brainstem, the axons of which directly innervate the tongue. Despite its fundamental importance, dysphagia (difficulty swallowing) and strategies to preserve swallowing function have seldom been studied in ALS models. ⋯ Hypoglossal motor neuron survival, swallowing function, and hypoglossal motor output were assessed in Sprague-Dawley rats after intralingual injection of either CTB-SAP (25 g) or unconjugated CTB and SAP (controls) into the genioglossus muscle. CTB-SAP treated rats exhibited significant (p ≤ 0.05) deficits vs. controls in: (1) lick rate (6.0 ± 0.1 vs. 6.6 ± 0.1 Hz; (2) hypoglossal motor output (0.3 ± 0.05 vs. 0.6 ± 0.10 mV); and (3) hypoglossal motor neuron survival (398 ± 34 vs. 1018 ± 41 neurons). Thus, this novel, inducible model of hypoglossal motor neuron death mimics the dysphagia phenotype that is observed in ALS rodent models, and will allow us to study strategies to preserve swallowing function.
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Wobbler mice are experimental models for amyotrophic lateral sclerosis. As such they show motoneuron degeneration, motor deficits, and astrogliosis and microgliosis of the spinal cord. Additionally, Wobbler mice show increased plasma, spinal cord and brain corticosterone levels and focal adrenocortical hyperplasia, suggesting a pathogenic role for glucocorticoids in this disorder. ⋯ Treatment of Wobbler mice with CORT 113176 reversed the abnormalities of motoneurons and down-regulated proinflammatory mediators and glial reactivity. Expression of glutamate transporters GLT1 and GLAST mRNAs and GLT1 protein was significantly enhanced over untreated Wobblers. In summary, antagonism of GR with CORT 113176 prevented neuropathology and showed anti-inflammatory and anti-glutamatergic effects in the spinal cord of Wobbler mice.
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1). ⋯ Neither SINE compounds nor leptomycin B, a separate XPO1 inhibitor, enhanced nuclear TDP43 levels, while depletion of XPO1 or other exportins had little effect on TDP43 localization, suggesting that no single exporter is necessary for TDP43 export. Supporting this hypothesis, we find overexpression of XPO1, XPO7 and NXF1 are each sufficient to promote nuclear TDP43 egress. Taken together, our results indicate that redundant pathways regulate TDP43 nuclear export, and that therapeutic prevention of cytoplasmic TDP43 accumulation in ALS/FTD may be enhanced by targeting several overlapping mechanisms.