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

We studied exonic trinucleotide repeats and expression of androgen receptor (AR) gene in the spinal cord from an autopsied patient with X-linked spinal and bulbar muscular atrophy (SBMA). Forty-nine CAG triplet repeats were found in tissues from the spinal cord, cerebrum, cerebellum, cardiac muscle and bladder, while there were 20-24 CAG repeats in these tissues from control subjects, consisting of three patients with amyotrophic lateral sclerosis (ALS) and three patients with lung cancer. Thus, mitotic instability of the AR gene in SBMA may not occur at the level of somatic cells. To determine whether expression of the AR gene in the spinal cord of SBMA differs from that in control subjects, we used quantitative reverse transcriptase (RT)-PCR and Western blot. AR mRNA and protein were detected in the spinal cord from the patient with SBMA, but the levels of both AR mRNA and protein were less than those from the patients with ALS in whom the loss of motor neurons was similar to findings in the patient with SBMA. These findings suggest that structural alteration plus a reduced level of AR in the spinal cord are involved in the pathogenesis of SBMA, resulting in degeneration of motor neurons.
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PMID:Exonic trinucleotide repeats and expression of androgen receptor gene in spinal cord from X-linked spinal and bulbar muscular atrophy. 751 6

Levels of creatine kinase MB isoform (CKMB) can be elevated in patients with myopathy, neuropathy, skeletal muscle injury, or renal failure in the absence of myocardial injury. These elevated CKMB levels make it difficult to identify cardiac involvement in conditions that can be associated with a variety of cardiac abnormalities or with symptoms that mimic them. Cardiac troponin I (cTnI), a myocardial regulatory protein, has a high specificity for cardiac muscle and can be used to clarify the etiology of CKMB elevations in such patients. In this report, four patients with diverse causes for increased CKMB levels are discussed with respect to cill.The first three patients, with tentative diagnoses of mixed connective tissue disease, amyotrophic lateral sclerosis, and polymyositis presented with increasing shortness of breath, tachycardia, nonspecific electrocardiogram changes, high creative kinase, and CKMB levels. A normal cTnI helped exclude a diagnosis of a cardiac cause of their symptoms. Patient 4 had a scleroderma variant and experienced sudden, fatal, cardiac decompensation caused by a dilated cardiomyopathy, accompanied by an increased cTnl.The cTnI is a reliable, specific, and quick wav of excluding or determining cardiac involvement in patients with connective tissue disease. As this test is inexpensive and becoming increasingly available, it could become the test of choice, especially in scenarios in which urgent management decisions are needed.
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PMID:Troponin I Assessment of Cardiac Involvement in Patients With Connective Tissue Disease and an Elevated Creatine Kinase MB Isoform Report of Four Cases and Review of the Literature. 1907 68

Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1(G93A) similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca(2+) accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1(G93A) transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.
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PMID:A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo. 2409 95

Cellular accumulation of repetitive RNA occurs in several dominantly-inherited genetic disorders. Expanded CUG, CCUG or GGGGCC repeats are expressed in myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), or familial amyotrophic lateral sclerosis, respectively. Expanded repeat RNAs (ER-RNAs) exert a toxic gain-of-function and are prime therapeutic targets in these diseases. However, efforts to quantify ER-RNA levels or monitor knockdown are confounded by stable structure and heterogeneity of the ER-RNA tract and background signal from non-expanded repeats. Here, we used a thermostable group II intron reverse transcriptase (TGIRT-III) to convert ER-RNA to cDNA, followed by quantification on slot blots. We found that TGIRT-III was capable of reverse transcription (RTn) on enzymatically synthesized ER-RNAs. By using conditions that limit cDNA synthesis from off-target sequences, we observed hybridization signals on cDNA slot blots from DM1 and DM2 muscle samples but not from healthy controls. In transgenic mouse models of DM1 the cDNA slot blots accurately reflected the differences of ER-RNA expression across different transgenic lines, and showed therapeutic reductions in skeletal and cardiac muscle, accompanied by improvements of the DM1-associated splicing defects. TGIRT-III was also active on CCCCGG- and GGGGCC-repeats, suggesting that ER-RNA analysis is feasible for several repeat expansion disorders.
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PMID:Detection of expanded RNA repeats using thermostable group II intron reverse transcriptase. 2903 54

Our previous study found that microRNA-21a-5p (miR-21a-5p) knockdown could improve the recovery of motor function after spinal cord injury in a mouse model, but the precise molecular mechanism remains poorly understood. In this study, a modified Allen's weight drop was used to establish a mouse model of spinal cord injury. A proteomics approach was used to understand the role of differential protein expression with miR-21a-5p knockdown, using a mouse model of spinal cord injury without gene knockout as a negative control group. We found that after introducing miR-21a-5p knockdown, proteins that played an essential role in the regulation of inflammatory processes, cell protection against oxidative stress, cell redox homeostasis, and cell maintenance were upregulated compared with the negative control group. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified enriched pathways in both groups, such as the oxidative phosphorylation pathway, which is relevant to Parkinson's disease, Huntington's disease, Alzheimer's disease, and cardiac muscle contraction. We also found that miR-21a-5p could be a potential biomarker for amyotrophic lateral sclerosis, as miR-21a-5p becomes deregulated in this pathway. These results indicate successful detection of some important proteins that play potential roles in spinal cord injury. Elucidating the relationship between these proteins and the recovery of spinal cord injury will provide a reference for future research of spinal cord injury biomarkers. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Shandong University of China on March 5, 2014.
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PMID:Comparative proteomes change and possible role in different pathways of microRNA-21a-5p in a mouse model of spinal cord injury. 3259 53