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)

The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol beta-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin-dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.
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PMID:Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex. 1215 76

To clarify the controversy concerning whether the cell death of motor neurons in ALS is apoptosis, we investigated the expression of Apaf-1 and caspase-9 mRNA in spinal cord tissue obained at autopsy from patients with ALS and controls using RT-PCR; the presence of in situ nuclear DNA fragmentation in motor neurons by the TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method; and immunocytochemical localization of Apaf-1 and caspase-3, which are known as promotors of apoptotic processes. Although Apaf-1 and caspase-9 mRNAs levels were increased in ALS, Apaf-1 immunoreactivity (IR) showed no significant difference between ALS and the control, and caspase-3 IR was not observed in ALS motoneurons, casting doubt on the notion that motor neurons in ALS undergo death by the classic apoptotic pathway. Although TUNEL-positive motor neurons were frequently observed in the anterior horn in ALS, these neurons always showed an atrophic cell body with a shrunken and pyknotic nucleus, indicating that they were at the terminal stage of degeneration. No apoptotic bodies were seen. These findings suggest that the mechanism of motor neuronal cell death in ALS might not be apoptosis, but some other as yet unidentified mechanism.
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PMID:Is motoneuronal cell death in amyotrophic lateral sclerosis apoptosis? 1638 89