Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The association between dementia and hip fracture was studied in a representative sample of 85-year olds (N = 485). The diagnosis of dementia was made according to the DSM-III-R. The prevalence of hip fracture was obtained by history and inspection of the hip. Bone mineral density was measured with dual photon absorptiometry of the right calcaneus. Hip fracture was associated with both Alzheimer's disease (p < 0.01) and vascular dementia (p < 0.01) in women, but not in men. Among women with dementia, the rate of hip fracture was more than twice that found in the general population (32.7% vs 13.6%). Bone density was not associated with dementia or hip fracture. Body mass index and body weight were lower in women with dementia and in women with hip fracture. The prevalence of hip fracture was also increased in subjects who used psychotropic drugs, especially tricyclic antidepressants. A logistic multiple regression analysis showed that dementia, use of antidepressants and gender independently contributed to hip fracture. The reason why subjects with dementia are at increased risk for hip fractures may be that these subjects have a defective neuromuscular regulation, gait apraxia, use more antidepressants, and have a lower body mass index. Another explanation of the association may be that surgery and anesthesia give rise to systemic hypotension that leads to cerebral hypoperfusion and ischemic and neuronal death in vulnerable brain areas, and as a consequence may lead to dementia or worsen the symptoms in subjects already affected by dementia.
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PMID:A population-based study on the association between dementia and hip fractures in 85-year olds. 886 94

Hip fractures are common and devastating events. The apolipoprotein E*4 (APOE) allele, associated with Alzheimer's disease, has also been associated with osteoporosis in hemodialysis patients. We prospectively studied 1750 women, age >/=65 years, who underwent measurements of hip and calcaneal bone mineral density (BMD), were typed for APOE and followed for approximately 7.0 years for the occurrence of fractures and falls. Women with at least one APOE*4 allele had an increased risk of hip fracture, relative hazard (RH) (95% confidence interval) = 1.90 (1.05-3.41) and wrist fracture, RH = 1.67 (1.01-2.77) compared with women without APOE*4, even after adjusting for age, cognitive function, falling, and BMD. The effect of APOE*4 on hip fracture was greatest among women with additional (>/=3) other risk factors. Women with an APOE*4 allele were also likely to report a maternal history of fracture. The average number of falls per year did not differ by APOE*4: 0.46 for APOE*4 women and 0.41 for women without an APOE*4 allele. Women with an APOE*4 allele experienced greater weight loss which contributed to faster rates of bone loss. We conclude that women with the APOE*4 polymorphism are at substantially increased risk of hip and wrist fracture that is not explained by bone density, impaired cognitive function, or falling. Possible alternate explanations include an effect of APOE on vitamin K, bone turnover, or weight loss. The APOE polymorphism may be a candidate gene for hip fractures among community dwelling nondemented women.
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PMID:Apolipoprotein E polymorphism: A new genetic marker of hip fracture risk--The Study of Osteoporotic Fractures. 1040 18

The ubiquitin/proteasome system has been proposed to play an important role in Alzheimer's disease (AD) pathogenesis. However, the critical factor(s) modulating both amyloid-beta peptide (Abeta) neurotoxicity and ubiquitin/proteasome system in AD are not known. We report the isolation of an unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2, as a mediator of Abeta toxicity. The expression of E2-25K/Hip-2 was upregulated in the neurons exposed to Abeta(1-42) in vivo and in culture. Enzymatic activity of E2-25K/Hip-2 was required for both Abeta(1-42) neurotoxicity and inhibition of proteasome activity. E2-25K/Hip-2 functioned upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta(1-42) toxicity. Further, the ubiquitin mutant, UBB+1, a potent inhibitor of the proteasome which is found in Alzheimer's brains, was colocalized and functionally interacted with E2-25K/Hip-2 in mediating neurotoxicity. These results suggest that E2-25K/Hip-2 is a crucial factor in regulating Abeta neurotoxicity and could play a role in the pathogenesis of Alzheimer's disease.
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PMID:Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity. 1452 3

Ubiquitin-positive deposits are histopathologically found in patients with Alzheimer's disease (AD). It is not understood why ubiquitin is accumulated in intra- and extra-cellular deposits or how it is involved in AD pathogenesis. Interestingly, recent evidence, including studies of E2-25K/Hip-2, has elucidated the molecular mechanism of the ubiquitin-proteasome system (UPS) malfunction in AD. The neurotoxicity and proteasome inhibition by Abeta, a main cause of AD pathogenesis, are mediated by increased E2-25K/Hip-2 in the brains of patients with AD. Furthermore, E2-25K/Hip-2 is required for the neurotoxicity that is mediated by a ubiquitin B mutant (UBB+1), which is a potent inhibitor of proteasomes that is found in patients with AD. Intensive research is required to identify the components of the UPS that are involved in AD pathogenesis.
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PMID:Alzheimer's disease meets the ubiquitin-proteasome system. 1551 83

Hip fracture is among the most common causes of acute immobilization in elderly patients, and elderly patients with hip fracture are at high risk for a subsequent hip fracture. At baseline, both groups had high serum concentrations of ionized calcium, high urinary deoxypyridinoline (DPD) concentrations, suggesting immobilization-induced hypercalcemia. We previously showed deficiency of vitamins D and K(1) causes reduced bone mineral density (BMD) in female Alzheimer's disease (AD) patients. In a random and prospective study of AD patients, 100 patients received 45 mg menatetrenone, 1,000 IU ergocalciferol and 600 mg calcium daily for 2 years, and the remaining 100 (untreated group) did not. Treatment with MK-4 and vitamin D(2) with calcium supplements increases the BMD in elderly female patients with AD and leads to the prevention of nonvertebral fractures. The risk of hip fracture after stroke is 2 to 4 times as high as that in age-matched healthy controls. Hyperhomocysteinemia is a risk factor for both ischemic stroke and osteoporotic fractures in elderly persons. Randomized, controlled, double-blinded study of 628 consecutive elderly hemiplegic patients at least 1 year following first ischemic stroke. Patients were assigned to daily oral treatment with 5 mg of folate and 1,500 microg of mecobalamin or double placebos, and 559 completed the 2 year follow up. Plasma homocysteine levels in the decreased by 38% in the treatment group and increased by 31% in the placebo group. The number of the hip fractures per 1,000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (p<0.001). In this Japanese population with a high baseline fracture risk, combined treatment with folate and vitamin B(12) is safe and effective in reducing the risk of a hip fracture in elderly stroke patients. Because of limited study power, the relative risk reduction may only be around 0.5.
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PMID:[Immobilization and hip fracture]. 1714 29

Accumulation of the hyperphosphorylated tau is a hallmark pathological event for the formation of neurofibrillary tangles in Alzheimer disease (AD). Until now, there is no effective way to antagonize this accumulation. Recently, it has been reported that carboxyl terminus of Hsc70-interacting protein (CHIP) is the specific tau E3 ligase and it mediates tau degradation in vitro. However, the nature of CHIP on in vivo tau degradation is not fully understood. Here, we demonstrated that hippocampal transfection of CHIP plasmid in rats could reach a time-dependent elevated expression of CHIP mRNA and protein in 24 h. Concomitantly, expression of exogenous CHIP could promote the degradation of the hyperphosphorylated tau induced by overactivation of glycogen synthase kinase-3 (GSK-3) or inhibition of protein phosphatase-2A (PP-2A) in the rat brains and N2A cells. CHIP also degraded tau in normal rats regardless the phosphorylation status of tau proteins. Though CHIP overexpression was not able to improve significantly the spatial memory retention deficits induced by overactivation of GSK-3, it did not cause significant damage to the memory function in normal rats. These results suggest that CHIP may degrade tau both in physiological and pathological conditions without affecting the behavior of the rats, implying that overexpression of CHIP may antagonize tau accumulation in the AD brains.
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PMID:Carboxyl terminus of heat-shock cognate 70-interacting protein degrades tau regardless its phosphorylation status without affecting the spatial memory of the rats. 1830 57

Amyloid-beta (Abeta) neurotoxicity is believed to contribute to the pathogenesis of Alzheimer's disease (AD). Previously we found that E2-25K/Hip-2, an E2 ubiquitin-conjugating enzyme, mediates Abeta neurotoxicity. Here, we report that E2-25K/Hip-2 modulates caspase-12 activity via the ubiquitin/proteasome system. Levels of endoplasmic reticulum (ER)-resident caspase-12 are strongly up-regulated in the brains of AD model mice, where the enzyme colocalizes with E2-25K/Hip-2. Abeta increases expression of E2-25K/Hip-2, which then stabilizes caspase-12 protein by inhibiting proteasome activity. This increase in E2-25K/Hip-2 also induces proteolytic activation of caspase-12 through its ability to induce calpainlike activity. Knockdown of E2-25K/Hip-2 expression suppresses neuronal cell death triggered by ER stress, and thus caspase-12 is required for the E2-25K/Hip-2-mediated cell death. Finally, we find that E2-25K/Hip-2-deficient cortical neurons are resistant to Abeta toxicity and to the induction of ER stress and caspase-12 expression by Abeta. E2-25K/Hip-2 is thus an essential upstream regulator of the expression and activation of caspase-12 in ER stress-mediated Abeta neurotoxicity.
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PMID:E2-25K/Hip-2 regulates caspase-12 in ER stress-mediated Abeta neurotoxicity. 1871 Sep 20

Myocardin, a coactivator of serum response factor (SRF), plays a critical role in the differentiation of vascular smooth muscle cells (SMCs). However, the molecular mechanisms regulating myocardin stability and activity are not well defined. Here we show that the E3 ligase C terminus of Hsc70-interacting protein (CHIP) represses myocardin-dependent SMC gene expression and transcriptional activity. CHIP interacts with and promotes myocardin ubiquitin-mediated degradation by the proteasome in vivo and in vitro. Furthermore, myocardin ubiquitination by CHIP requires its phosphorylation. Importantly, CHIP overexpression reduces the level of myocardin-dependent SMC contractile gene expression and diminishes arterial contractility ex vivo. These findings for the first time, to our knowledge, demonstrate that CHIP-promoted proteolysis of myocardin plays a key role in the physiological control of SMC phenotype and vessel tone, which may have an important implication for pathophysiological conditions such as atherosclerosis, hypertension, and Alzheimer's disease.
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PMID:CHIP represses myocardin-induced smooth muscle cell differentiation via ubiquitin-mediated proteasomal degradation. 1923 36

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme that is important in maintaining the cellular redox state and regulating protein degradation. The NQO1 polymorphism C609T has been associated with increased susceptibility to various age-related pathologies. We show here that NQO1 protein level is regulated by the E3 ligase STUB1/CHIP (C terminus of Hsc70-interacting protein). NQO1 binds STUB1 via the Hsc70-interacting domain (tetratricopeptide repeat domain) and undergoes ubiquitination and degradation. We demonstrate here that the product of the C609T polymorphism (P187S) is a stronger STUB1 interactor with increased susceptibility to ubiquitination by the E3 ligase STUB1. Furthermore, age-dependent decrease of STUB1 correlates with increased NQO1 accumulation. Remarkably, examination of hippocampi from Alzheimer disease patients revealed that in half of the cases examined the NQO1 protein level was undetectable due to C609T polymorphism, suggesting that the age-dependent accumulation of NQO1 is impaired in certain Alzheimer disease patients.
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PMID:E3 ligase STUB1/CHIP regulates NAD(P)H:quinone oxidoreductase 1 (NQO1) accumulation in aged brain, a process impaired in certain Alzheimer disease patients. 2122 Apr 32

Hip fracture is an important step in the autonomy evolution in elderly. As gait is particularly jeopardised after such a traumatism, cognition may also be acutely impaired. Elderly post-surgery delirium is frequent, but chronic progression of cognitive impairment and dementia may occur. The concept of cognitive reserve is crucial for understanding risk factors of post-surgery delirium in elderly. The more the cognitive reserve is decreased before such a traumatism, the higher the delirium and dementia progression risk is. A neurodegenerative disease such as Alzheimer's disease may be clinically silent prior the traumatic event, and may decompensate soon after as the cognitive reserve is not sufficient anymore. Dementia may then lead to progressive autonomy loss. A systematic interdisciplinary approach is needed to prevent frail patients from delirium, and to early cure it to decrease the risk of long-term autonomy loss.
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PMID:[Post-surgery cognitive disorders: prevention, diagnosis and treatment strategies]. 2182 81


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