Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence indicates that neuroinflammation is a key event in amyotrophic lateral sclerosis (ALS). However, the precise impact of inflammation on motor neurons remains elusive. By using organotypic spinal cord slice cultures, we demonstrate that exposure to lipopolysaccharide (LPS) led to the demise of motor neurons in a dose- and time- dependent manner, whereas interneurons were impaired relatively mildly. The ultrastructure of motor neurons showed extensive vacuolation and swollen mitochondria. Motor neurons lacked the expression of calretinin, and BAPTA-AM, an intracellular calcium chelator, ameliorated motor neuron injury, indicating that the low capacity of calcium buffering may partially account for the vulnerability of motor neurons. NADPH oxidase was activated upon LPS challenge, and apocynin, the selective inhibitor of this enzyme, prevented inflammation-mediated toxicity to motor neurons, suggesting that NADPH oxidase may play a critical role in motor neuron death caused by LPS-induced inflammation.
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PMID:The NADPH oxidase is involved in lipopolysaccharide-mediated motor neuron injury. 1859 79

In amyotrophic lateral sclerosis (ALS) spinal cords, diffuse myelin pallor (dMP) in the anterolateral columns (ALCs) beyond the corticospinal tracts has been frequently observed; however, its origin still remains to be elucidated. To address this issue, we focused on calretinin (CR) and parvalbumin (PV), since these buffer calcium-binding proteins (CaBP) are predominantly expressed in axons in the ALCs of neurologically normal human spinal white matter. Immunohistochemical methods revealed that numbers of both CR-immunoreactive (ir) and PV-ir axons were significantly lower in ALS patients' spinal cords with dMP compared to those in controls. In ALS patients' spinal cords without dMP, there were also significant reductions in the number of these CaBP-ir axons compared to controls. In contrast, the number of CR-ir neurons in the spinal gray matter did not differ significantly among ALS patients and controls. These findings suggest that a loss of CaBP-ir axons may precede the development of dMP in ALS patients' spinal cords, and the dying back mechanism would underlie this phenomenon.
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PMID:Loss of calretinin- and parvalbumin-immunoreactive axons in anterolateral columns beyond the corticospinal tracts of amyotrophic lateral sclerosis spinal cords. 2376 61

Increasing evidence indicates an excitatory/inhibitory imbalance may have a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Impaired inhibitory circuitry is consistently reported in the motor cortex of both familial and sporadic patients, closely associated with cortical hyperexcitability and ALS onset. Inhibitory network dysfunction is presumably mediated by intra-cortical inhibitory interneurons, however, the exact cell types responsible are yet to be identified. In this study we demonstrate dynamic changes in the number of calretinin- (CR) and neuropeptide Y-expressing (NPY) interneurons in the motor cortex of the familial hSOD1G93A ALS mouse model, suggesting their potential involvement in motor neuron circuitry defects. We show that the density of NPY-populations is significantly decreased by ~17% at symptom onset (8 weeks), and by end-stage disease (20 weeks) is significantly increased by ~30%. Conversely, the density of CR-populations is progressively reduced during later symptomatic stages (~31%) to end-stage (~36%), while CR-expressing interneurons also show alteration of neurite branching patterns at symptom onset. We conclude that a differential capacity for interneurons exists in the ALS motor cortex, which may not be a static phenomenon, but involves early dynamic changes throughout disease, implicating specific inhibitory circuitry.
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PMID:Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS. 2829 53

TDP-43 is an RNA-binding protein important for many aspects of RNA metabolism. Abnormal accumulation of TDP-43 in the cytoplasm of affected neurons is a pathological hallmark of the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Several transgenic mouse models have been generated that recapitulate defects in TDP-43 accumulation, thus causing neurodegeneration and behavioural impairments. While aging is the key risk factor for neurodegenerative diseases, the specific effect of aging on phenotypes in TDP-43 transgenic mice has not been investigated. Here, we analyse age-dependent changes in TDP-43 transgenic mice that displayed impaired memory. We found the accumulation of abundant poly-ubiquitinated protein aggregates in the hippocampus of aged TDP-43 transgenic mice. Intriguingly, the aggregates contained some interneuron-specific proteins such as parvalbumin and calretinin, suggesting that GABAergic interneurons were degenerated in these mice. The abundance of aggregates significantly increased with age and with the overexpression of TDP-43. Gene array analyses in the hippocampus and other brain areas revealed dysregulation in genes linked to oxidative stress and neuronal function in TDP-43 transgenic mice. Our results indicate that the interneuron degeneration occurs upon aging, and TDP-43 accelerates age-dependent neuronal degeneration, which may be related to the impaired memory of TDP-43 transgenic mice.
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PMID:TDP-43 accelerates age-dependent degeneration of interneurons. 2909 7


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