Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0233565 (bradykinesia)
 2,352 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-N-Oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) are chemically related excitant amino acids isolated from the seed of Lathyrus sativus (BOAA) and Cycas circinalis (BMAA), consumption of which has been linked to lathyrism (an upper motor neuron disorder) and Guam amyotrophic lateral sclerosis (ALS), respectively. Both diseases are associated with degeneration of motor neurons. Experimentally, single doses of BOAA or BMAA induce seizures in neonatal mice and postsynaptic neuronal oedema and degeneration in explants of mouse spinal cord and frontal cortex. Preliminary studies show that these behavioural and pathological effects are differentially blocked by glutamate-receptor antagonists. In macaques, several weeks of daily oral doses of BOAA produce clinical and electrophysiological signs of corticospinal dysfunction identical to those seen in comparably well-nourished animals receiving a fortified diet based on seed of Lathyrus sativus. By contrast, comparable oral dosing with BMAA precipitates tremor and weakness, bradykinesia and behavioural changes, with conduction deficits in the principal motor pathway. BOAA and BMAA (or a metabolite thereof) are the first members of the excitotoxin family to have been shown to possess chronic motor-system toxic potential. These observations provide a rational basis for searching for comparable endogenous neurotoxins in sporadic and inherited forms of human motor neuron disease.
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PMID:Discovery and partial characterization of primate motor-system toxins. 310 39

Environmental toxins have been implicated in the etiology of Parkinson's disease. Recent findings of defects in the ubiquitin-proteasome system in hereditary and sporadic forms of the illness suggest that environmental proteasome inhibitors are candidate PD-inducing toxins. Here, we systemically injected six doses of naturally occurring (epoxomicin) or synthetic (Z-lle-Glu(OtBu)-Ala-Leu-al [PSI]) proteasome inhibitors into adult rats over a period of 2 weeks. After a latency of 1 to 2 weeks, animals developed progressive parkinsonism with bradykinesia, rigidity, tremor, and an abnormal posture, which improved with apomorphine treatment. Positron emission tomography demonstrated reduced carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) binding to dopaminergic nerve terminals in the striatum, indicative of degeneration of the nigrostriatal pathway. Postmortem analyses showed striatal dopamine depletion and dopaminergic cell death with apoptosis and inflammation in the substantia nigra pars compacta. In addition, neurodegeneration occurred in the locus coeruleus, dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. At neurodegenerative sites, intracytoplasmic, eosinophilic, alpha-synuclein/ubiquitin-containing, inclusions resembling Lewy bodies were present in some of the remaining neurons. This animal model induced by proteasome inhibitors closely recapitulates key features of PD and may be valuable in studying etiopathogenic mechanisms and putative neuroprotective therapies for the illness.
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PMID:Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. 1686 91

Mutations in presenilin 1 (PSEN1) are the most common cause of autosomal dominant Alzheimer's disease. Here, we report a 37-year-old male Korean patient carrying a PSEN1 p.Gly417Ala mutation with exceptionally early and severe presentations, including a wide range of atypical symptoms of rapid cognitive decline with a stooped posture, rigidity, and bradykinesia. Targeted next-generation sequencing of proband revealed a novel nucleotide substitution (c.1250G>C) in exon 12 of PSEN1 gene, altering glycine to alanine at 417 position. Three-dimensional protein structure prediction revealed that the variant may cause perturbations in the 8th transmembrane region, perturbing its functions from the increased hydrophobicity and size of alanine with decreased flexibility. Since several glycine>alanine substitutions in other PSEN1 transmembrane helices revealed aggressive Alzheimer's disease phenotypes, PSEN1 Gly417Ala may share a common pathogenic mechanism.
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PMID:Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism. 3018 Sep 83