UMLS:C0002736 - FACTA Search

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)

Matrix metalloproteinases (MMPs) were analyzed by immunohistochemistry and zymography in amyotrophic lateral sclerosis (ALS) and control brain and spinal cord specimens. Three major bands of enzyme activity (70, 100, and 130 kDa) were consistently observed and were subsequently identified as MMP-2 (70 kDa; also known as EC 3.4.24.24 or gelatinase A) and MMP-9 (100 and 130 kDa; also known as EC 3.4.24.35 or gelatinase B). Immunohistochemical studies established the presence of MMP-2 in astrocytes and MMP-9 in pyramidal neurons in the motor cortex and motor neurons in the spinal cord of ALS patients. Although a significant decrease in MMP-2 activity was noticed in the ALS motor cortex, statistically significant increases in MMP-9 (100-kDa) activity were observed in ALS frontal and occipital cortices (BA10 and 17) and all three spinal cord regions when compared with control specimens. The highest MMP-9 (100-kDa) activities in ALS were found in the motor cortex and thoracic and lumbar cord specimens. The abnormally high amount of MMP-9 and its possible release at the synapse may destroy the structural integrity of the surrounding matrix, thereby contributing to the pathogenesis of ALS.
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PMID:Matrix metalloproteinases in the neocortex and spinal cord of amyotrophic lateral sclerosis patients. 866 98

Proteolytic enzyme expression was studied by matrix metalloproteinases (MMP) immunoreactivity (-IR) in muscle biopsies from patients with amyotrophic lateral sclerosis (ALS), spinal muscle atrophy (SMA) and chronic axonal neuropathies (CANP). In normal muscle MMP-2-, MMP-7-, and MMP-9-IR was localized at neuromuscular junctions, in vessels and nerve branches. ALS biopsies of clinically non-affected muscles revealed neither MMP-2, -7-IR nor MMP-9-IR in atrophied myofibers. ALS-affected biopsies revealed MMP-9-IR, and to lesser extent MMP-2- and MMP-7-IR at normal sized and atrophied myofibers. Biopsies of SMA showed MMP-9- and MMP-7-IR at normal sized and atrophic myofibers, while MMP-2-IR was undetectable. In CANP MMP-9-IR was found at normal sized and atrophied myofibers. Distinct expression patterns of MMPs may thus reflect different stages of muscle denervation atrophy.
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PMID:Matrix metalloproteinases MMP-2, MMP-7 and MMP-9 in denervated human muscle. 1051 42

Matrix metalloproteinases (MMPs) are hypothesized to play an important role in the pathogenesis of several central nervous system disorders. Increased levels of expression of MMP-9 (gelatinase B) and MMP-2 (gelatinase A) have been observed in Alzheimer's disease, stroke, multiple sclerosis, and amyotrophic lateral sclerosis. This suggests an aberrant regulation of MMPs that could lead to inappropriate expression of MMP activity. To allow us to evaluate the effect of increased levels of active MMP-9 in the central nervous system, mutant forms of the enzyme were designed to autocatalytically remove the pro domain, yielding active enzyme. This was accomplished by modifying residues in the cysteine switch autoinhibitor region of the propeptide. Stable cell lines and transgenic mice that express G100L and D103N autoactive forms of human MMP-9 were developed to study the role of dysregulation of MMP-9 in disease.
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PMID:Engineering autoactivating forms of matrix metalloproteinase-9 and expression of the active enzyme in cultured cells and transgenic mouse brain. 1208 77

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS). Increased expression of MMP-9 and TIMPs has been reported in postmortem AD and ALS brain tissue, as well as in ALS cerebrospinal fluid (CSF) and plasma. Although individual studies of MMP and TIMP expression in CSF have included AD and ALS samples, there are no studies comparing the expression of these proteins between neurodegenerative diseases. We measured the levels of matrix metalloproteinases (MMPs)-2 and -9 and the tissue inhibitor of MMPs (e.g. TIMP-1 and TIMP-2) in CSF samples from patients with Parkinson's Disease (PD), Huntington's Disease (HD), AD and ALS as compared to age-matched control patients. There was constitutive expression of the proform of gelatinase A (proMMP-2) on zymography gels in all CSF samples. Unexpectedly, there was an additional gelatinolytic band at 130 kDa of unknown etiology in the CSF samples of patients with PD (61% of patients studied), AD (61%), HD (25%) and ALS (39%). Levels of TIMP-1 were significantly elevated in CSF samples from all disease groups. TIMP-2 was significantly increased in CSF of AD and HD patients. MMP-2 levels did not differ significantly between groups. These findings show that TIMPs are elevated in the CSF of patients with neurodegenerative diseases suggesting a potential role of these endogenous inhibitors of matrix metalloproteinases in neurodegenerative diseases.
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PMID:Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal fluid of neurodegenerative diseases. 1261 34

Matrix metalloproteinases (MMPs) may play a role in the pathophysiology of Alzheimer's disease (AD). MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) are elevated in postmortem brain tissue of AD patients. MMPs and TIMPs are found in neurons, microglia, vascular endothelial cells and leukocytes. The aim of this study was to determine whether circulating levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 are elevated in the plasma of AD patients. We compared AD patients to age- and gender-matched controls as well as to Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) patients. There was constitutive expression of gelatinase A (MMP-2), and gelatinase B (MMP-9), in all the samples as shown by zymographic analysis. Levels of MMP-9 were significantly (P=0.003) elevated in the plasma of AD patients as compared to controls. Plasma levels of MMP-2, TIMP-1 and TIMP-2 were unchanged. There were no significant changes of MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in PD and ALS samples. TIMP-1 and TIMP-2 were significantly correlated with MMP-9 in the AD patients. ApoE genotyping of plasma samples showed that levels of MMP-2, TIMP-1 and TIMP-2 and MMP-9 were not significantly different between the ApoE subgroups. These findings indicate that circulating levels of MMP-9 are increased in AD and may contribute to disease pathology.
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PMID:Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease. 1268 99

In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the MMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MMP inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05) prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days, mean +/- SD), however, administration at disease onset did not significantly improve survival time. Our experiments show that MMPs are expressed in an animal model of ALS and may play a role in the complex pathophysiologic changes. Early pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the animals which suggest a role of MMPs in the early phase of the disease.
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PMID:The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice. 1651 96

Amyotrophic lateral sclerosis (ALS) mainly affects the motor neurons but may also include other organs such as the skin. We aimed to determine whether matrix metalloproteinases could provide a link between neuronal degeneration and skin alterations in ALS. We measured CSF, serum and skin tissue MMP-2 and MMP-9 using ELISA and malondialdehyde (MDA), a marker of lipid peroxidation, using High Performance Liquid Chromatography (HPLC) in 54 ALS patients and 36 controls. We found CSF and skin MMP-9 to be elevated in ALS as compared to controls (p<0.001, p=0.03, respectively). We observed CSF MMP-9 to be highest in patients with a rapid progressive course of disease (p=0.008). In contrast, we found no significant differences of CSF, serum or skin concentrations of MMP-2 as compared to controls. CSF MMP-2 concentrations decreased with duration of disease (p=0.04, R=-0.31). MDA was elevated in serum of ALS (p<0.001), though no correlation with MMP-2 or MMP-9 was observed. Our findings indicate a general upregulation of MMP-9 in ALS. MMP-9 seems to play a role in both neurodegeneration and skin changes in ALS and could thus be a common factor linking otherwise distant aspects of disease pathology.
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PMID:Linking neuron and skin: matrix metalloproteinases in amyotrophic lateral sclerosis (ALS). 1952 50

Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease.
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PMID:Serum matrix metalloproteinase-9 activity is dysregulated with disease progression in the mutant SOD1 transgenic mice. 2009 66

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, which are present in central and peripheral nervous system. They are considered to be involved in the pathogenesis of several neurological diseases, as multiple sclerosis, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). The aim of the present study was to evaluate the application of the pattern recognition methods for the assessment of MMPs in serum of patients with ALS. Thirty patients with amyotrophic lateral sclerosis (ALS), in two subgroups: (i) with mild and (ii) severe progressing ALS, and 15 control healthy subjects were studied. The metalloproteinases MT-MMP-1, MMP-2, MMP-9 were examined. Additional variables (age of subjects and disease duration) were also analyzed by using a standard, parallel and hierarchical classifiers. Our results indicate that: (i) MMP-2 in serum may be an important marker for the evaluation of ALS progress; (ii) the set of two features {MT-MMP-1, MMP-9} may be helpful in differentiation between ALS and healthy subjects; (iii) the error rates obtained for the pair-wise linear classifier were similar to those received for the classifiers (standard, parallel, and hierarchical) based on k-NN rule. We conclude that the pattern recognition methods may be useful for the evaluation of significance MMPs as markers in neurodegenerative diseases, such as ALS.
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PMID:Evaluation of matrix metalloproteinases in serum of patients with amyotrophic lateral sclerosis with pattern recognition methods. 2013 51

We aimed to clarify the role of matrix metalloproteinases (MMP) as a possible link between neurodegeneration and skin pathology in ALS by determination of gelatinase MMP-2 and MMP-9 in spinal cord and skin of transgenic SOD1((G93A)) mice. To elucidate mechanisms influencing MMPs, markers of oxidative damage (malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and 8-hydroxy-2'-deoxyguanosine (8OH2'dG)) as well as cytokines (tumor necrosis factor alpha (TNF-alpha) and interleukin 1ss (IL-1ss)) were determined. We measured MMP-9, MMP-2, 3-NT, TNF-alpha, and IL-1ss using ELISA, MDA using High Performance Liquid Chromatography (HPLC) and 8OH2'dG using HPLC with electrochemical detection (HPLC-ECD) in SOD1 and WT. MMP-9 was elevated in spinal cord and skin of SOD1 at 90 days (p=0.009, p<0.001) and 120 days (p<0.01, p=0.04). MMP-2 was elevated in the spinal cord at 90 days (p=0.01) and in the skin at 120 days (p=0.039). We observed a correlation of MMP-9 in spinal cord and skin of SOD1 (p=0.04). MDA was elevated in the spinal cord of SOD1 at 90 and 120 days (p=0.00006, p=0.01) and 8OH2'dG at 90 days (p=0.048). IL-1ss was elevated in the spinal cord of SOD1 at 120 days (p=0.02). Our data confirms that gelatinase MMPs are a common factor linking neurodegeneration and skin changes in ALS. It suggests that oxidative stress and microglial-derived cytokines contribute to the elevation of gelatinase MMPs especially in later stages of disease. Our data raises the question whether the skin may function as a biomarker for specific aspects of disease pathology in ALS.
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PMID:MMP-2 and MMP-9 are elevated in spinal cord and skin in a mouse model of ALS. 2044 96

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