Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein-L-isoaspartyl methyltransferase (PIMT) is a putative protein repair enzyme, which methylates the alpha-carboxyl group of atypical L-isoaspartyl residues in aged proteins and converts them to normal L-aspartyl residues. Two splicing variants, PIMT-I and PIMT-II, have been reported, although their biological functions and specific subcellular substrates are still to be defined. We and another group have previously showed that PIMT-deficient mice succumbed to fatal epileptic seizures associated with an abnormal accumulation of isoaspartate (IsoAsp) in the brain. In the present study, we prepared two recombinant adenovirus vectors that contained PIMT-I or PIMT-II, respectively, in order to investigate the differential biological roles of PIMT-I and PIMT-II. These recombinant viruses differentially conferred PIMT-I or PIMT-II expressions in cultured neurons. Biochemical analyses showed that either of PIMT-I or PIMT-II effectively repaired the damaged proteins in PIMT-deficient neurons, but the concomitant expression failed to show an additive effect in the repair of IsoAsp. These results suggested that PIMT-I and PIMT-II might share a common biological function and/or subcellular substrates. In addition, we administered an adeno-PIMT-I vector into the brain of PIMT-deficient mice at embryonic day 14.5 by an exo-utero method to assess the biological effects in vivo. The result showed that recombinant adeno-PIMT improved the symptoms of PIMT-deficient mice in vivo, but only partially repaired IsoAsp in damaged proteins. The gene therapy presented in this report provided a better prognosis for the survival of PIMT-deficient mice than the previously reported anti-epileptic drug therapy. The results suggested a new reagent for gene therapy applicable to ageing-associated neurodegenerative disorders.
...
PMID:Adenoviral expression of protein-L-isoaspartyl methyltransferase (PIMT) partially attenuates the biochemical changes in PIMT-deficient mice. 1212 76

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. The disease occurs in early life with developmental delay or arrest and several neurological symptoms, e.g., seizures and dyskinesia. Both the deficiency of high-energy phosphates in neurons and the neurotoxic action of the accumulated metabolite guanidinoacetate (GAA) are candidate mechanisms for the pathophysiology of this disease. To examine a potential role of GAA accumulation, we analyzed the electrophysiological responses of neurons induced by GAA application in primary culture and acute murine brain slices. GAA evoked picrotoxin- and bicuculline-sensitive GABA(A) receptor-mediated chloride currents with an EC(50) of 167 microM in cortical neurons. Pathophysiologically relevant GAA concentrations hyperpolarized globus pallidus neurons and reduced their spontaneous spike frequency with an EC(50) of 15.1 microM. Furthermore, GAA acted as a partial agonist at heterologously expressed GABA(A) but not GABA(B) receptors. The interaction of GAA with neuronal GABA(A) receptors represents a candidate mechanism explaining neurological dysfunction in GAMT deficiency.
...
PMID:Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism. 1250 22

We report the case of a 23-year-old woman with velocardiofacial syndrome (VCFS) and a history of psychosis and seizures. She had been treated with conventional antipsychotic and antiepileptic drugs for 10 and 3 years, respectively. However, she continued to experience occasional hallucinations and paroxysmal jerking of the extremities. L-alpha-methyldopa 500 mg b.i.d. (later reduced to 250 mg t.i.d.) was added to her regimen. Hallucinations and seizures stopped shortly. Over the course of approximately 1 year, the previous medications were discontinued without recurrence of psychotic and epileptic symptoms. Eventually, improved mental functions and behaviour enabled her transition from living in a licensed residential facility to sharing a private residence with a partner. VCFS is associated with haploinsufficiency of catecholamine-methyltransferase, leading to excessive extraneuronal catecholamine concentrations. Alpha-Methyldopa inhibits catecholamine neurotransmission in a variety of ways. It is possible that the drug compensated for genetically disturbed catecholamine transmission thus achieving beneficial effects in this case.
...
PMID:Replacement of antipsychotic and antiepileptic medication by L-alpha-methyldopa in a woman with velocardiofacial syndrome. 1259 25

The protein L-isoaspartate (D-aspartate)-O-methyltransferase participates in the repair of age-induced protein damage by initiating the conversion of abnormal aspartyl residues within proteins to normal L-aspartyl residues. Previous studies have shown that mice deficient in the gene encoding this enzyme (Pcmt1-/-) accumulate damaged proteins, have altered levels of brain S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy), and suffer from epileptic seizures that result in death at an average age of about 42 days. In this study, we found that the behavior of Pcmt1-/- mice is abnormal in comparison to their wild-type (Pcmt1+/+) and heterozygous (Pcmt1+/-) littermates in two standard quantitative behavioral assays - the accelerating rotorod and the open-field test. On the accelerating rotorod, we found Pcmt1-/- mice actually perform significantly better than their heterozygous and wild-type littermates, a situation that has only been infrequently described in the literature and has not been described to date for epilepsy-prone mice. The Pcmt1-/- mice show, however, hyperactivity in the open-field test that becomes more pronounced with age, with a partial habituation with time in the chamber. Additionally, these mice demonstrate a strong thigmotaxic movement pattern. We present evidence that these phenotypes are not related to the alterations of the AdoMet/AdoHcy ratio in the brain and thus may be a function of the accumulation of damaged proteins. These results implicate a role for this enzyme in motor coordination and cerebellum development and suggest the importance of the function of the repair methyltransferase in hippocampal-dependent spatial learning.
...
PMID:Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase. 1521 14

Protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1) is a protein-repair enzyme, and mice lacking this enzyme accumulate damaged proteins in multiple tissues, die at an early age from progressive epilepsy and have an increased S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy) ratio in brain tissue. It has been proposed that the alteration of AdoMet and AdoHcy levels might contribute to the seizure phenotype, particularly as AdoHcy has anticonvulsant properties. To investigate whether altered AdoMet and AdoHcy levels might contribute to the seizures and thus the survivability of the repair-deficient mice, a folate-deficient amino acid-based diet was administered to the mice in place of a standard chow diet. We found that the low-folate diet significantly decreases the AdoMet/AdoHcy ratio in brain tissue and results in an almost threefold extension of mean life span in the protein repair-deficient mice. These results indicate that the increased AdoMet/AdoHcy ratio may contribute to the lowered seizure threshold in young PCMT1-deficient mice. However, mean survival was also extended almost twofold for mice on a control folate-replete amino acid-based diet compared to mice on the standard chow diet. Survival after 40 days was similar in the mice on the low- and high-folate amino acid-based diets, suggesting that the survival of older PCMT1-deficient mice is not affected by the higher brain AdoMet/AdoHcy ratio. Additionally, the surviving older repair-deficient mice have a significant increase in body weight when compared to age-matched normal mice, independent of the type of diet. This weight increase was not accompanied by an increase in consumption levels, indicating that the repair-deficient mice may also have an altered metabolic state.
...
PMID:Diet-dependent survival of protein repair-deficient mice. 1611 44

The accumulation of potentially deleterious L-isoaspartyl linkages in proteins is prevented by the action of protein L-isoaspartyl O-methyltransferase, a widely distributed enzyme that is particularly active in mammalian brain. Methyltransferase-deficient (knock-out) mice exhibit greatly increased levels of isoaspartate and typically succumb to fatal epileptic seizures at 4-10 weeks of age. The link between isoaspartate accumulation and the neurological abnormalities of these mice is poorly understood. Here, we demonstrate that synapsin I from knock-out mice contains 0.9 +/- 0.3 mol of isoaspartate/mol of synapsin, whereas the levels in wild-type and heterozygous mice are undetectable. Transgenic mice that selectively express methyltransferase only in neurons show reduced levels of synapsin damage, and the degree of reduction correlates with the phenotype of these mice. Isoaspartate levels in synapsin from the knock-out mice are five to seven times greater than those in the average protein from brain cytosol or from a synaptic vesicle-enriched fraction. The isoaspartyl sites in synapsin from knock-out mice are efficiently repaired in vitro by incubation with purified methyltransferase and S-adenosyl-L-methionine. These findings demonstrate that synapsin I is a major substrate for the isoaspartyl methyltransferase in neurons and suggest that isoaspartate-related alterations in the function of presynaptic proteins may contribute to the neurological abnormalities of mice deficient in this enzyme.
...
PMID:Synapsin I is a major endogenous substrate for protein L-isoaspartyl methyltransferase in mammalian brain. 1644 4

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis. Magnetic resonance imaging showed high signal bilaterally in the globus pallidus on T2-weighted images. Mitochondrial respiratory chain studies revealed low complex I activity (in muscle 0.052 nmol NADH oxidized per min per unit citrate synthase, controls 0.166 +/- 0.047; in fibroblasts 0.080 nmol NADH oxidized per min per unit citrate synthase, controls 0.197 +/- 0.034). The true diagnosis was suspected at 21 months of age because of persistent low plasma and urine creatinine concentrations. GAMT activity was undetectable in fibroblasts and compound heterozygous mutations were found in the GAMT gene (c.327G>A and c.522G>A). The patient was treated with creatine, dietary arginine restriction and ornithine supplements. Her movement disorder and seizures resolved but she still has severe cognitive impairment and no expressive language. The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in mitochondrial encephalopathies. It is important to establish the correct diagnosis because specific treatment is available.
...
PMID:Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. 1717 76

Explosive running is a reliable initial component of audiogenic seizures (AS) induced by acoustic stimulation in genetically prone rodents. This profound locomotor activation is usually considered as a convulsive manifestation of AS although some studies attribute running to a panic-like response. Increase in central histamine activity has been shown to suppress clonic and tonic seizures. The present study examined the involvement of histaminergic mechanisms in the expression of running component of AS. Metoprine, an inhibitor of histamine-N-methyltransferase, was used to increase brain histamine level. Running was induced 4 and 24 h after intraperitoneal injection of metoprine or vehicle in rats of different strains. A brief sound stimulation elicited running followed by clonic-tonic convulsions in Krushinsky-Molodkina (KM) rats or running alone in AS-prone Wistar and WAG/Rij rats. In KM rats, metoprine exerted opposite effects on the main phases of AS. It increased the duration of running and decreased the duration and severity of clonic-tonic convulsions. In Wistar rats, metoprine produced a remarkable aggravation of running leading to its 2- to 3-fold prolongation. In WAG/Rij rats with mixed seizures (absence and audiogenic), the drug caused either aggravation or suppression of running behavior. These results suggest specific role for histaminergic system in the expression of behavioral components of AS. Suppressive role of histamine in clonic-tonic seizures is associated with facilitation of running suggesting specific effects of histamine on brainstem neuronal networks underlying these phases of AS. Possible roles of histaminergic mechanisms in seizure, motor and aversive aspects of sound-induced running are discussed.
...
PMID:Histaminergic modulation of acoustically induced running behavior in rats. 1736 90

Proteins are subject to various types of spontaneous modifications that can disrupt their structures with sometimes adverse affects on biological activity. The formation of L-isoaspartyl (or D-aspartyl) residues, through either the deamidation of asparagine or dehydration of aspartate, is one of the most frequent types of deterioration occurring under physiological conditions. Protein L-isoaspartate/D-aspartate o-methyltransferase (PIMT) is a conserved and ubiquitous enzyme that participates in the repair of various isomerized proteins. PIMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine onto the alpha-carboxyl group of an L-isoaspartyl (or the beta-carboxyl group of an D-aspartyl) residue, which initiates the conversion of this residue to an L-aspartyl residue. PIMT-deficient mice have been shown to die at a mean age of 42 days from progressive epileptic seizures with grand mal and myoclonus. Although PIMT-deficiency clearly leads to the accumulation of isomerized proteins, it is currently unclear how this causes progressive epilepsy in PIMT-deficient mice. As a first step towards understanding this, we developed a new assay to measure PIMT activity in cell lysates. Additionally, we isolated PIMT knockdown cells from HEK293 cells that were stably transfected with a PIMT small interfering RNA expression vector. PIMT activities were significantly decreased in the PIMT knockdown cells, and analysis of the transfectants revealed that MEK and ERK were hyperactivated after cell stimulation with epidermal growth factor (EGF). These results indicate that the ability to repair L-isoaspartyl-(or D-aspartyl-) containing proteins is important for the maintenance of normal MEK-ERK signaling.
...
PMID:[Role of isomerized protein repair enzyme, PIMT, in cellular functions]. 1805 81

l-Aspartyl (l-Asp) and l-asparaginyl residues in proteins isomerize or racemize to d,l-isoaspartyl (d,l-isoAsp) or d-aspartyl (d-Asp) residues during protein aging. These atypical aspartyl residues can interfere with the biological function of the protein and lead to cellular dysfunction. Protein l-isoaspartyl (d-aspartyl) methyltransferase (PIMT) is a repair enzyme that facilitates conversion of l-isoAsp and d-Asp to l-Asp. PIMT deficient mice exhibit accumulation of l-isoAsp in several tissues and die, on average, 12 days after birth from progressive epileptic seizures with grand mal and myoclonus features. However, little is known about the molecular mechanisms by which accumulation of the aberrant residues leads to cellular abnormalities. In this study, we established PIMT-knockdown cells using a short interfering RNA expression system and characterized the resultant molecular abnormalities in intracellular signaling pathways. PIMT-knockdown cells showed significant accumulation of proteins with isomerized residues, compared to control cells. In the PIMT-knockdown cells, Raf-1, MEK, and ERK, members of the MAPK cascade, were hyperphosphorylated after EGF stimulation compared to control cells. These results suggest that PIMT repair of abnormal proteins is necessary to maintain normal MAPK signaling.
...
PMID:Suppression of protein l-isoaspartyl (d-aspartyl) methyltransferase results in hyperactivation of EGF-stimulated MEK-ERK signaling in cultured mammalian cells. 1838 Dec


<< Previous 1 2 3 4 Next >>

---