Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.1 (NADPH-diaphorase)
 3,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms of human mutant superoxide dismutase-1 (mSOD1) toxicity to motor neurons (MNs) are unresolved. We show that MNs in G93A-mSOD1 transgenic mice undergo slow degeneration lacking similarity to apoptosis structurally and biochemically. It is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. p53 and p73 are activated in degenerating MNs, but without nuclear import. The MN death is independent of activation of caspases-1, -3, and -8 or apoptosis-inducing factor within MNs, with a blockade of apoptosis possibly mediated by Aven up-regulation. MN swelling is associated with compromised Na,K-ATPase activity and aggregation. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of superoxide, nitric oxide, and peroxynitrite than MNs in control mice. Nitrated and aggregated cytochrome c oxidase subunit-I and alpha-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible nitric oxide synthase (iNOS)-like immunoreactivity, and iNOS gene deletion extends significantly the life span of G93A-mSOD1 mice. Prior to MN loss, spinal interneurons degenerate. These results identify novel mechanisms for mitochondriopathy and MN degeneration in amyotrophic lateral sclerosis (ALS) mice involving blockade of apoptosis, accumulation of MN mitochondria with enhanced toxic potential from distal terminals, NOS localization in MN mitochondria and peroxynitrite damage, and early degeneration of alpha-synuclein(+) interneurons. The data support roles for oxidative stress, protein nitration and aggregation, and excitotoxicity as participants in the process of MN degeneration caused by mSOD1.
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PMID:Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. 1709 94

A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein alpha-synuclein (alpha-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant a-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant alpha-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53-->Thr (A53T)-mutant alpha-Syn and Gly-93-->Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated a-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.
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PMID:Transgenic mice with human mutant genes causing Parkinson's disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration. 1759 75

The enteric nervous system (ENS) poses the intrinsic innervation of the gastrointestinal tract and plays a critical role for all stages of postnatal life. There is increasing scientific and clinical interest in acquired or age-related gastrointestinal dysfunctions that can be manifested in diseases such as gut constipation or fecal incontinence. In this study, we sought to analyze age-dependent changes in the gene expression profile of the human ENS, particularly in the myenteric plexus. Therefore, we used the laser microdissection technique which has been proven as a feasible tool to analyze distinct cell populations within heterogeneously composed tissues. Full biopsy gut samples were prepared from children (4-12 months), middle aged (48-58 years) and aged donors (70-95 years). Cryosections were histologically stained with H&E, the ganglia of the myenteric plexus identified and RNA isolated using laser microdissection technique. Quantitative PCR was performed for selected neural genes, neurotransmitters and receptors. Data were confirmed on protein level using NADPH-diaphorase staining and immunohistochemistry. As result, we demonstrate age-associated alterations in site-specific gene expression pattern of the ENS. Thus, in the adult and aged distal parts of the colon a marked decrease in relative gene expression of neural key genes like NGFR, RET, NOS1 and a concurrent increase of CHAT were observed. Further, we detected notable regional differences of RET, CHAT, TH, and S100B comparing gene expression in aged proximal and distal colon. Interestingly, markers indicating cellular senescence or oxidative stress (SNCA, CASP3, CAT, SOD2, and TERT) were largely unchanged within the ENS. For the first time, our study also describes the age-dependent expression pattern of all major sodium channels within the ENS. Our results are in line with previous studies showing spatio-temporal differences within the mammalian ENS.
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PMID:Age-related gene expression analysis in enteric ganglia of human colon after laser microdissection. 2536 Jan 10