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)

We measured the activity of transglutaminase (TG), a Ca(2+)-dependent enzyme and a biochemical marker of cell degeneration, in the adult rat spinal cord after unilateral occlusion of a branch of the dorsal spinal artery, and compared it to the enzyme activity in the tissue on the contralateral side without ischemic damage. The affected half of the spinal cord showed a significant rise in intrinsic (endogenous) TG activity one day after ischemic insult while no apparent morphological changes were observed in the tissue. However, the enzymic activity on the affected side gradually decreased to reach the level in the non-affected tissue, accompanying severe degeneration of neuronal cells at 7 days after the surgery, then it declined to nearly half the level in the intact tissue 30 days after the operation. We also determined the TG activity in transverse sections of the human spinal cord obtained at autopsy from 5 amyotrophic lateral sclerosis (ALS) and 9 non-ALS patients. TG activity in thoracic and lumbar cords was markedly low in ALS patients not only in ventral and lateral regions but also in the dorsal portion. These findings imply that the reduced TG activity in the ALS spinal cord is one of the characteristic features of the disease reflecting exhaustion of the enzyme in the tissue resulting from degeneration of the spinal neurons through cross-linkage of soluble intraneuronal cytoplasmic proteins.
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PMID:Alteration of transglutaminase activity in rat and human spinal cord after neuronal degeneration. 874 5

Oxidative stress is suggested as a significant causative factor for pathogenesis of neuronal degeneration on spinal cord of human ALS. We measured some enzymic activities implicating neuronal degeneration process, such as cytochrome c oxidase (CO), superoxide dismutase (SOD), and transglutaminase (TG) in spinal cord of an animal model of ALS, motor neuron degeneration (Mnd) mouse, a mutant that exhibits progressive degeneration of lower spinal neurons during developmental growth, and compared them with age-matched control C57BL/6 mice. CO activity in Mnd spinal cord decreased during early postnatal period, while SOD activity reduced in later stage. In Mnd tissue, TG activity in lumbar cord was increasing during early stage, but tended to decline in later period gradually. These biochemical alterations became evident prior to the appearance of clinical motor dysfunction which were observed in later stages of development in Mnd spinal cord.
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PMID:Alteration of enzymatic activities implicating neuronal degeneration in the spinal cord of the motor neuron degeneration mouse during postnatal development. 956 92

Human amyotrophic lateral sclerosis (ALS), a typical motor neuron disease, is characterized pathologically by selective degenerative loss of motoneurons in the CNS. We have demonstrated significant reductions of neurotransmitter-related factors, such as acetylcholine-(ACh)-synthesizing enzyme activity and glutamate and aspartate contents in the ALS, compared to the non-ALS spinal cord obtained at autopsy. We have also shown considerable reductions in activities of cytochrome-c oxidase (CO), an enzyme contributing to aerobic energy production, and transglutaminase (TG), a Ca(2+)-dependent marker enzyme for tissue degeneration, in the ALS spinal cord. We found marked increases in fragmented glial fibrillary acidic protein (GFAP), a filamentous protein specifically associated with reactive astrocytes, in the ALS spinal cord relative to non-ALS tissue. These biochemical results corresponded well to pathomor-phological neuronal degenerative loss and reactive proliferation of astroglial components in the ALS spinal cord tissue. However, these results only indicate the final pathological and biochemical outcomes of ALS, and it is difficult to follow up cause and process in the ALS spinal cord during progression of the disease. Therefore, we used an animal model closely resembling human ALS, motor neuron degeneration (Mnd) mutant mice, a subline of C57BL/6 that shows late-onset progressive degeneration of lower motor neurons with paralytic gait beginning around 6.5 mo of age, to follow the biochemical and pathological alterations during postnatal development. We detected significant decreases in CO activity during early development and in activity of superoxide dismutase (SOD), an antioxidant enzyme, in later stages in Mnd mutant spinal cord tissue. TG activity in the Mnd spinal cord showed gradual increases during early development reaching a maximum at 5 mo, and then tending to decrease thereafter. Amounts of fragmented GFAPs increased continuously during postnatal development in Mnd spinal cord. These biochemical changes were observed prior to the appearance of clinical motor dysfunctions in the Mnd mutant mice. Such biochemical analyses using appropriate animal models will be useful for inferring the origin and progression of human ALS.
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PMID:Neurochemical changes in the spinal cord in degenerative motor neuron diseases. 964 76

The activity of transglutaminase (TGase), a marker enzyme for tissue degeneration, was examined in serum and cerebrospinal fluid (CSF) obtained from patients with sporadic amyotrophic lateral sclerosis (SALS), and compared to those from patients without SALS. When the serum TGase activity values from SALS patients were compared against the 'ALS-scale', which is used for clinical evaluation of the progression of ALS, the TGase activity values were higher at the initial stage of the disease than in non-ALS subjects, whereas they became extremely low at the late stage of ALS. The TGase activity in the CSF taken at later than middle stage from ALS patients with definite clinical motor dysfunctions was significantly lower than in that from non-ALS subjects. We have previously demonstrated marked reduction of tissue TGase activity in all regions of spinal cord tissue transections from ALS patients, not only in ventral but also lateral and dorsal regions, relative to that in non-ALS patients. These results suggest that some TGase may be leaked out of the spinal cord tissue into the CSF and then into the blood-stream during the progression of ALS, and the enzymic activity finally becomes depleted at the terminal stages of the disease when most of the spinal motor neuronal perikarya have been destroyed.
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PMID:Transglutaminase activity in serum and cerebrospinal fluid in sporadic amyotrophic lateral sclerosis: a possible use as an indicator of extent of the motor neuron loss. 966 78

Neurofilamentous conglomerates (NfCg), as axonal spheroids or conglomerates in motoneurons, are the histopathologic hallmarks for early stages of amyotrophic lateral sclerosis (ALS). We hypothesize that NfCg may be formed by post-translational modifications of altered Nf proteins that include: (1) hyperphosphorylation, (2) glycosylation (or glycoxidation), (3) nitration, (4) ubiquitination and/or (5) crosslinking by the Ca++-dependent transglutaminase (TGase). These, as well as other changes, are predicted to be initiated or accentuated by oxidative damage. The damaged Nf proteins then activate cascades of intracellular protein degradation which include ATP-dependent ubiquitin/proteasome proteolysis. Other proteolytic systems, either Ca++-dependent or independent, may also be activated, such as serine and cysteine protease systems. These enzymes, either lysosomal or non-lysosomal may also participate in the degradation of damaged Nf proteins being balanced by their cognate inhibitors. Protein complexes formed by these protease=inhibitor systems, along with damaged Nf proteins, may accumulate within the cell bodies as neuronal inclusions, since a number of intracellular inclusions are found in motor neurons in ALS. In the current study, we investigated the involvement of serine proteases and their serpins in NfCg formation. Pairs of three serine proteases (trypsin, chymotrypsin and thrombin) and their cognate serpins (alpha1-anti-trypsin, alpha1-anti-chymotrypsin, and protease nexin I) were probed in motoneurons with their antibodies for both NfCg and inclusions. Positive immunoreactivities for all serine proteases and their cognate serpins support the contention that the imbalance of serine proteases and internalized serpins may have a role in formation of NfCg and inclusions, and hence, the pathogenesis of ALS.
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PMID:Serpin=serine protease-like complexes within neurofilament conglomerates of motoneurons in amyotrophic lateral sclerosis. 985 54

Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) must invoke newly developing technologies if we are to discover pharmaceutical treatments that will help a significant population of patients with the disease. The focus of ALS research over the last 10 years has been on reactive oxygen species (ROS) and glutamate excitotoxicity, resulting in several clinical trials and the launch of the only drug currently available for the treatment of ALS, riluzole. Unfortunately, the therapeutic benefits have been minimal, at best, and the prognosis for patients with ALS has not improved beyond very modest retardation of the disease course. By emphasising ROS and glutamate excitotoxicity, current ALS research has only partially been able to attenuate the rate of motor decline and neuronal loss associated with this illness. Clues to additional therapeutic potentialities will come from an increased understanding of the mode of cell death (apoptotic or other) and the pathways leading to neuronal demise. If death is apoptotic, inhibiting caspases may be useful. The regulatory modifications for cell death at the molecular level remain to be determined and exploited to prevent neuronal loss, although novel pathways have been recently elucidated that impact on protein aggregation and processing. Oxidative stress, seen in both familial and sporadic forms of ALS, may be only one post-translational mechanism likely to affect specific proteins essential for the health and stability of motor neurons. Protein cross-linking by transglutaminase paralleling that may lead to defects in proteasome function may also be a significant mechanism. The latest capabilities to screen protein changes in specific cells represent the kinds of advances needed to combat ALS in the third millennium.
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PMID:Prospects for the pharmacotherapy of amyotrophic lateral sclerosis : old strategies and new paradigms for the third millennium. 1287 54

Candida dubliniensis is a pathogenic yeast species closely related to Candida albicans. However, it is less frequently associated with human disease and displays reduced virulence in animal models of infection. Here comparative genomic hybridization was used in order to assess why C. dubliniensis is apparently less virulent than C. albicans. In these experiments the genomes of the two species were compared by co-hybridizing C. albicans microarrays with fluorescently labelled C. albicans and C. dubliniensis genomic DNA. C. dubliniensis genomic DNA was found to hybridize reproducibly to 95.6 % of C. albicans gene-specific sequences, indicating a significant degree of nucleotide sequence homology (> 60 %) in these sequences. The remaining 4.4 % of sequences (representing 247 genes) gave C. albicans/C. dubliniensis normalized fluorescent signal ratios that indicated significant sequence divergence (< 60 % homology) or absence in C. dubliniensis. Sequence divergence was identified in several genes (confirmed by Southern blot analysis and sequence analysis of PCR products) with putative virulence functions, including the gene encoding the hypha-specific human transglutaminase substrate Hwp1p. Poor hybridization of C. dubliniensis genomic DNA to the array sequences for the secreted aspartyl proteinase-encoding gene SAP5 also led to the finding that SAP5 was absent in C. dubliniensis and that this species possesses only one gene homologous to SAP4 and SAP6 of C. albicans. In addition, divergence and absence of sequences in several gene families was identified, including a family of HYR1-like GPI-anchored proteins, a family of genes homologous to a putative transcriptional activator (CTA2) and several ALS genes. This study has confirmed the close relatedness of C. albicans and C. dubliniensis and has identified a subset of unique C. albicans genes that may contribute to the increased prevalence and virulence of this species.
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PMID:Comparative genomics using Candida albicans DNA microarrays reveals absence and divergence of virulence-associated genes in Candida dubliniensis. 1547 Jan 15

Type 2 transglutaminase (TG2) is a calcium-dependent acyltransferase which also undergoes a GTP-binding/GTPase cycle even though it lacks any obvious sequence similarity with canonical GTP-binding (G) proteins. As an enzyme which is responsible for the majority of transglutaminase (TG) activity in the brain, TG2 is likely to play a modulatory role in nervous system development and has regulatory effect on neuronal cell death as well. Most importantly, numerous studies have presented data demonstrating that dysregulation of TG2 may contribute to the pathogenesis of many neurodegenerative disorders, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis as well as nervous system injuries. Although TG2's involvement in these disease conditions is strongly suggested by various findings, such as the increase of TG2 mRNA expression, protein level and TG activity in the pathological process of these neurodegenerative disorders, as well as the therapeutic effect of TG2 genetic deletion in animal models of Huntington's disease, the precise mechanism underlying TG2's role remain unclear. TG2 was originally proposed to contribute to the pathogenesis of these diseases by facilitating the formation of insoluble protein aggregates, however recent findings clearly indicate that this is likely not the case. Nonetheless, there is data to suggest that TG2 may play a role in neurodegenerative processes by stabilizing toxic oligomers of the disease-relevant proteins, although further studies are needed to validate these initial in vitro findings.
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PMID:Transglutaminase 2 in neurodegenerative disorders. 1712 46