Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Guadeloupe, there is an abnormally high frequency of atypical parkinsonism. Only one-third of the patients that develop parkinsonian symptoms were reported to present the classical features of idiopathic Parkinson disease and one-third a syndrome resembling progressive supranuclear palsy (PSP). The others were unclassifiable, according to established criteria. We carried out a cross-sectional study of 160 parkinsonian patients to: (i) define more precisely the clinical phenotypes of the PSP-like syndrome and the parkinsonism that was considered unclassifiable in comparison with previously known disorders; (ii) define the neuropsychological and brain imaging features of these patients; (iii) evaluate to what extent a candidate aetiological factor, the mitochondrial complex I inhibitor annonacin contained in the fruit and leaves of the tropical plant Annona muricata (soursop) plays a role in the neurological syndrome. Neuropsychological tests and MRI were used to classify the patients into those with Parkinson's disease (31%), Guadeloupean PSP-like syndrome (32%), Guadeloupean parkinsonism-dementia complex (PDC, 31%) and other parkinsonism-related disorders (6%). Patients with a PSP-like syndrome developed levodopa-resistant parkinsonism, associated with early postural instability and supranuclear oculomotor dysfunction. They differed, however, from classical PSP patients by the frequency of tremor (>50%), dysautonomia (50%) and the occurrence of hallucinations (59%). PDC patients had levodopa-resistant parkinsonism associated with frontosubcortical dementia, 52% of these patients had hallucinations, but, importantly, none had oculomotor dysfunction. The pattern of neuropsychological deficits was similar in both subgroups. Cerebral atrophy was seen in the majority of the PSP-like and PDC patients, with enlargement of the third ventricle and marked T2-hypointensity in the basal ganglia, particularly the substantia nigra. Consumption of soursop was significantly greater in both PSP-like and PDC patients than in controls and Parkinson's disease patients. In conclusion, atypical Guadeloupean parkinsonism comprises two forms of parkinsonism and dementia that differ clinically by the presence of oculomotor signs, but have similar cognitive profiles and neuroimaging features, suggesting that they may constitute a single disease entity, and both were similarly exposed to annonaceous neurotoxins, notably annonacin.
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PMID:Atypical parkinsonism in Guadeloupe: a common risk factor for two closely related phenotypes? 1730 92

Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1 -/- ) mice, a model of infantile CLN1 disease. Glutamate uptake inhibition by t-PDC (L-trans-pyrrolidine-2,4-dicarboxylic acid) or Zn2+-induced general mitochondrial dysfunction caused similar toxicity in WT and Ppt1 -/- cultures. Ppt1 -/- neurons, however, were more sensitive to mitochondrial complex I inhibition by MPP+ (1-methyl-4-phenylpyridinium), and had significantly decreased sensitivity to chemical anoxia induced by the mitochondrial complex IV inhibitor, sodium azide. Our results indicate that PPT1 deficiency causes alterations in the mitochondrial respiratory chain.
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PMID:Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia. 2772 92

The underlying anticancer effects of butyrate, an end-product of the intestinal microbial fermentation of dietary fiber, remain elusive. Here, we report that butyrate promotes cancer cell apoptosis by acting as a SIRT3 inhibitor. Butyrate inhibits SIRT3 both in cultured cells and in vitro. Butyrate-induced PDHA1 hyperacetylation relieves the inhibitory phosphorylation of PDHA1 at serine 293, thereby activating an influx of glycolytic intermediates into the tricarboxylic acid (TCA) cycle and reversing the Warburg effect. Meanwhile, butyrate-induced hyperacetylation inactivates complex I of the electron transfer chain and prevents the utilization of TCA cycle intermediates. These metabolic stresses promote apoptosis in hyperglycolytic cancer cells, such as HCT116p53-/- cells. SIRT3 deacetylates both PDHA1 and complex I. Genetic ablation of Sirt3 in mouse hepatocytes abrogated the ability of butyrate to induce apoptosis. Our results identify a butyrate-mediated anti-tumor mechanism and indicate that the combined activation of PDC and inhibition of complex I is a novel tumor treatment strategy.
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PMID:Butyrate induces apoptosis by activating PDC and inhibiting complex I through SIRT3 inactivation. 2926 7