Mitochondrial enzyme deficiencies in Down's syndrome

Prince, Jonathan A.; Jia, Shenshan; Båve, Ullvi; Annerén, Göran; Oreland, Lars

doi:10.1007/bf02260938

Cited by 51 publications

(29 citation statements)

References 34 publications

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“…However, we have previously reported that there is a high correlation between white blood cell MAO-B activity and trbc MAO activity (r = 0.98; n = 20). 32 Therefore, we used nuclear extracts from human white blood cells to perform gel-shift analyses of the occurrence of proteins that bind to the 0.15-kb sequence of the MAOB promoter. Samples were obtained from male, non-smoking volunteers selected for a wide spread of trbc MAO activity.…”

Section: Transcriptional Regulation Of Trbc Maomentioning

confidence: 99%

Genetic mechanisms of behavior—don't forget about the transcription factors

et al. 2001

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Major changes in psychiatric phenotypes due to genetic factors are seldom the result of single gene polymorphisms, but more often the result of several genetic mechanisms. In this millennium article we discuss the notion that the expression of numerous candidate genes could be regulated by the same transcription factors, and that polymorphisms in transcription factor genes might explain some phenotypes. We describe recent results of studies on the biological marker thrombocyte monoamine oxidase (trbc MAO) and the transcription factor AP-2␤. Low levels of trbc MAO is associated with temperamental characteristics such as sensation seeking and impulsiveness, and the enzyme is genetically regulated by specific transcriptional mechanisms. Transcription factor AP-2␤ is important for the development of midbrain structures and AP-2␤ has several binding sites in the regulatory regions of genes encoding key proteins in the monoamine transmitter systems. We have recently shown AP-2␤ to be linked to personality, binge-eating disorder, treatment with antidepressant drugs, and also to trbc MAO. Regardless of whether transcriptions factors, such as AP-2␤, regulate the expression of eg, the number of monoamine neurons or a variety of candidate genes within the monoamine systems, or both, we would like to emphasize the role of transcription factors, besides polymorphisms in monoaminergic candidate genes, when explaining inter-individual differences in temperament and psychiatric vulnerability. Molecular Psychiatry (2001) 6, 503-510.

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Section: Transcriptional Regulation Of Trbc Maomentioning

confidence: 99%

Genetic mechanisms of behavior—don't forget about the transcription factors

et al. 2001

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“…COX dysfunction also increases free radicals, reduces energy stores, and disturbs amyloid metabolism (Gabuzda et al, 1994;Mutisya et al, 1994;Smith et al, 1996;Davis et al, 1997). COX dysfunction is associated with Down's syndrome; many Down's syndrome patients develop AD (Prince et al, 1994;Busciglio and Yanker, 1995). Mutations in mitochondrial COX genes also seem to segregate with late-onset AD .…”

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confidence: 99%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

242

140

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Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to 0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4,5-triphosphate (InsP 3 )-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP 3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. ␤-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.

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“…Therefore, in this syndrome, the metabolism is down-regulated by lowered basal metabolic rate [20][21][22]. Our study shows a relationship between lack of ER XbaI site and obesity in both genders.…”

Section: Discussionmentioning

confidence: 76%

Impact of ER gene polymorphisms on overweight and obesity in Down Syndrome

2008

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AbstractThe impact of ER XbaI and PvuII α gene polymorphisms on overweight and obesity were studied in 77 subjects with Down Syndrome (DS), of which 32 were children (18 boys, 14 girls), mean age 8.7 ± 2.3 years, and 45 adolescents (28 boys, 17 girls) mean age 14 ± 2.5 years. Their lifestyle was compared to 40 healthy age-matched controls. DS subjects had significant lesser physical activity than controls (p<0.05) and a lower caloric intake than the recommended requirements, which was significantly lesser than controls (p<0.05). Body Mass Index (BMI), Arm Circumference (AC) and Triceps Skinfold Thickness (TST) were significantly higher in DS subjects than controls (p<0.05), while metabolic and cardiovascular parameters were not significantly different between the groups (p>0.05). The frequency of ER genotypes in DS subjects was compared with the healthy controls, finding that there was a high prevalence of XXER genotype in DS subjects. Children and adolescents with DS, lacking ER XbaI site, showed significantly higher BMI and body fat distribution than other XbaI genotypes. The lack of ER XbaI site can indicate added risk of obesity in DS. No differences in metabolic and cardiovascular parameters were observed among ER genotypes. However, childhood obesity is associated with increased cardiovascular risk.

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Mitochondrial enzyme deficiencies in Down's syndrome

Cited by 51 publications

References 34 publications

Genetic mechanisms of behavior—don't forget about the transcription factors

Genetic mechanisms of behavior—don't forget about the transcription factors

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Impact of ER gene polymorphisms on overweight and obesity in Down Syndrome

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