Is there a role for copper in neurodegenerative diseases?

Copper is an essential metal in living organisms; thus, the maintenance of adequate copper levels is of vital importance and is highly regulated. Dysfunction of copper metabolism leading to its excess or deficiency results in severe ailments. Two examples of illnesses related to alterations in copper metabolism are Menkes and Wilson diseases. Several proteins are involved in the maintenance of copper homeostasis, including copper transporters and metal chaperones. In the last several years, the beta-amyloid-precursor protein (beta-APP) and the prion protein (PrP(C)), which are related to the neurodegenerative disorders Alzheimer and prion diseases respectively, have been associated with copper metabolism. Both proteins bind copper through copper-binding domains that also have been shown to reduce copper in vitro. Moreover, this ability to reduce copper is associated with a neuroprotective effect exerted by the copper-binding domain of both proteins against copper in vivo. In addition to a functional link between copper and beta-APP or PrP(C), evidence suggests that copper has a role in Alzheimer and prion diseases. Here, we review the evidence that supports both, the role of beta-APP and PrP(C), in copper metabolism and the putative role of copper in neurodegenerative diseases.     

Prion protein expression level alters regional copper, iron and zinc content in the mouse brain

The central role of the prion protein (PrP) in a family of fatal neurodegenerate diseases has garnered considerable research interest over the past two decades. Moreover, the role of PrP in neuronal development, as well as its apparent role in metal homeostasis, is increasingly of interest. The host-encoded form of the prion protein (PrP(C)) binds multiple copper atoms via its N-terminal domain and can influence brain copper and iron levels. The importance of PrP(C) to the regulation of brain metal homeostasis and metal distribution, however, is not fully understood. We therefore employed synchrotron-based X-ray fluorescence imaging to map the level and distributions of several key metals in the brains of mice that express different levels of PrP(C). Brain sections from wild-type, prion gene knockout (Prnp(-/-)) and PrP(C) over-expressing mice revealed striking variation in the levels of iron, copper, and even zinc in specific brain regions as a function of PrP(C) expression. Our results indicate that one important function of PrP(C) may be to regulate the amount and distribution of specific metals within the central nervous system. This raises the possibility that PrP(C) levels, or its activity, might regulate the progression of diseases in which altered metal homeostasis is thought to play a pathogenic role such as Alzheimer's, Parkinson's and Wilson's diseases and disorders such as hemochromatosis.     

Mitochondria removal by autophagy

Mitochondrial dysfunction has severe cellular consequences and is linked with neurodegenerative diseases and aging. Maintaining a healthy population of mitochondria is thus essential for proper cellular homeostasis. Several strategies have evolved to prevent and limit mitochondria damage, and macroautophagy plays a role in degrading superfluous or severely damaged mitochondria. Selective removal of mitochondria by autophagy (termed mitophagy) has been extensively studied recently in both yeast and mammalian cells. In this review, we summarize our current knowledge of mitophagy. We also compare the molecular process of mitophagy with other types of specific autophagic pathways and discuss its biological importance.     

The ALK-1/Smad1 pathway in cardiovascular physiopathology. A new target for therapy?

Activin receptor-like kinase-1 or ALK-1 is a type I cell surface receptor for the transforming growth factor-β (TGF-β) family of proteins. The role of ALK-1 in endothelial cells biology and in angiogenesis has been thoroughly studied by many authors. However, it has been recently suggested a possible role of ALK-1 in cardiovascular homeostasis.ALK-1 is not only expressed in endothelial cells but also in smooth muscle cells, myofibroblast, hepatic stellate cells, chondrocytes, monocytes, myoblasts, macrophages or fibroblasts, but its role in these cells have not been deeply analyzed. Due to the function of ALK-1 in these cells, this receptor plays a role in several cardiovascular diseases. Animals with ALK-1 haploinsufficiency and patients with mutations in Acvrl1 (the gene that codifies for ALK-1) develop type-2 Hereditary Hemorrhagic Telangiectasia. Moreover, ALK-1 heterozygous mice develop pulmonary hypertension. Higher levels of ALK-1 have been observed in atherosclerotic plaques, suggesting a possible protector role of this receptor. ALK-1 deficiency is also related to the development of arteriovenous malformations (AVMs). Besides, due to the ability of ALK-1 to regulate cell proliferation and migration, and to modulate extracellular matrix (ECM) protein expression in several cell types, ALK-1 has been now demonstrated to play an important role in cardiovascular remodeling.In this review, we would like to offer a complete vision of the role of ALK-1 in many process related to cardiovascular homeostasis, and the involvement of this protein in the development of cardiovascular diseases, suggesting the possibility of using the ALK-1/smad-1 pathway as a powerful therapeutic target.     

Regucalcin as a potential biomarker for metabolic and neuronal diseases

Regucalcin was initially discovered in 1978 as a regulatory protein in calcium signaling. The regucalcin gene, which is localized on the X chromosome, is found in vertebrate and invertebrate species. Regucalcin has been shown to play a pivotal role in cell regulation: maintaining of intracellular calcium homeostasis, suppressions of signal transduction, inhibition of translational protein synthesis, nuclear deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, regulation of gene expression, and anti-effects on proliferation and apoptosis in many cell types. The expression of the regucalcin gene and its protein has been shown to alter with various metabolic diseases, and regucalcin plays an important role in the development of many pathophysiologic states. Serum regucalcin has been found to increase with liver injury, and also urinary regucalcin is elevated with kidney damage, suggesting a useful tool as biomarker for diagnosis. Moreover, regucalcin has been shown to be good tool in early diagnosis for Alzheimer’s disease and other brain diseases. This review will discuss a significance of regucalcin as a clinical biomarker in various diseases.     

Calreticulin, a multifunctional Ca2+ binding chaperone of the endoplasmic reticulum.

Calreticulin is a ubiquitous endoplasmic reticulum Ca2+ binding chaperone. The protein has been implicated in a variety of diverse functions. Calreticulin is a lectin-like chaperone and, together with calnexin, it plays an important role in quality control during protein synthesis, folding, and posttranslational modification. Calreticulin binds Ca2+ and affects cellular Ca2+ homeostasis. The protein increases the Ca2+ storage capacity of the endoplasmic reticulum and modulates the function of endoplasmic reticulum Ca2+-ATPase. Calreticulin also plays a role in the control of cell adhesion and steroid-sensitive gene expression. Recently, the protein has been identified and characterized in higher plants but its precise role in plant cells awaits further investigation.     

Immunoproteasome expression is induced in mesial temporal lobe epilepsy

Immunoproteasome has been associated to neurodegenerative and autoimmune diseases as a marker and regulator of inflammatory mechanisms. Its expression in the brain may occur upon neuroinflammation in different cell types and affect a variety of homeostatic and inflammatory pathways including the oxidized protein clearance and the self-antigen presentation. In the present study we investigated the immunoproteasome expression in hippocampi and cortex of patients affected by different histopathological forms of pharmaco-resistent mesial temporal lobe epilepsy. We identified a pathology-specific pattern of immunoproteasome expression, which could provide insight into the complex neuroinflammatory pathogenic components of this disease.     

Zinc, copper, and carnosine attenuate neurotoxicity of prion fragment PrP106-126

Prion diseases are progressive neurodegenerative diseases that are associated with the conversion of normal cellular prion protein (PrP(C)) to abnormal pathogenic prion protein (PrP(SC)) by conformational changes. Prion protein is a metal-binding protein that is suggested to be involved in metal homeostasis. We investigated here the effects of trace elements on the conformational changes and neurotoxicity of synthetic prion peptide (PrP106-126). PrP106-126 exhibited the formation of β-sheet structures and enhanced neurotoxicity during the aging process. The co-existence of Zn(2+) or Cu(2+) during aging inhibited β-sheet formation by PrP106-126 and attenuated its neurotoxicity on primary cultured rat hippocampal neurons. Although PrP106-126 formed amyloid-like fibrils as observed by atomic force microscopy, the height of the fibers was decreased in the presence of Zn(2+) or Cu(2+). Carnosine (β-alanyl histidine) significantly inhibited both the β-sheet formation and the neurotoxicity of PrP106-126. Our results suggested that Zn(2+) and Cu(2+) might be involved in the pathogenesis of prion diseases. It is also possible that carnosine might become a candidate for therapeutic treatments for prion diseases.     

Roles of sirtuins in the regulation of antioxidant defense and bioenergetic function of mitochondria under oxidative stress

Abstract

In addition to serving as the power house of mammalian cells, mitochondria are crucial for the maintenance of cellular homeostasis in response to physiological or environmental changes. Several lines of evidence suggest that posttranslational modification (PTM) of proteins plays a pivotal role in the regulation of the bioenergetic function of mitochondria. Among them, reversible lysine acetylation of mitochondrial proteins has been established as one of the key mechanisms in cellular response to energy demand by modulating the flux of a number of key metabolic pathways. In this article, we focus on the role of Sirt3-mediated deacetylation in: (1) flexibility of energy metabolism, (2) activation of antioxidant defense, and (3) maintenance of cellular redox status in response to dietary challenge and oxidative stress. We suggest that oxidative stress-elicited down-regulation of Sirt3 plays a role in the pathophysiology of diabetes, cardiac hypotrophy, mitochondrial diseases, and age-related diseases. Besides, the physiological role of newly identified lysine acylation mediated by Sirt5 and its biochemical effects on oxidative metabolism are also discussed. Moreover, we have integrated the regulatory function of several protein kinases that are involved in the phosphorylation of mitochondrial enzymes during oxidative stress. Finally, the functional consequence of the synergistic regulation through diverse protein modifications is emphasized on the maintenance of the bioenergetic homeostasis and metabolic adaptation of the animal and human cells. Together, we have provided an updated review of PTM in mitochondrial biology and their implications in aging and human diseases through an intricate regulation of energy metabolism under oxidative stress.     

RAGE and glyoxalase in kidney disease

Glycation is an important reaction in the regulation of physiological state. When poorly controlled, however, glycation can also result in the accumulation of glycated proteins (advanced glycation endproducts; AGEs) in the body. This AGE accumulation is termed glycative stress, and is an established pathological factor: to date, glycative stress has been closely associated with not only kidney diseases, but also kidney aging. Accumulating evidence demonstrates that the progression of renal tubular damage and tubular aging are often correlated with activation of the receptor for the AGE (RAGE)-AGE pathway or decreased activity of glyoxalase 1, which is an anti-glycation enzyme to lower glycative stress. Further, glycative stress exacerbates the derangement of protein homeostasis: the posttranslationally modified proteins by glycation often lose or gain their functions. Such deranged protein homeostasis leads to endoplasmic reticulum (ER) stress, a state of ER dysfunction in which the quality control of proteins is defective, as well as to induction of its stress signal, the unfolded protein response (UPR), in the kidney. The lowering of glycative stress via modulation of RAGE-AGE axis or glyoxalase 1 activity is beneficial for tubular homeostasis and the subsequent prevention and treatment of kidney disease, suggesting the possibility of novel therapeutic approaches which target glycative stress. In this review, we focused on the impact of glycative stress in the kidney, especially the role of RAGE and glyoxalase 1. Further we also discuss the crosstalk between glycative stress and ER stress in their effect on protein homeostasis.     

Create and preserve: Proteostasis in development and aging is governed by Cdc48/p97/VCP

The AAA-ATPase Cdc48 (also called p97 or VCP) acts as a key regulator in proteolytic pathways, coordinating recruitment and targeting of substrate proteins to the 26S proteasome or lysosomal degradation. However, in contrast to the well-known function in ubiquitin-dependent cellular processes, the physiological relevance of Cdc48 in organismic development and maintenance of protein homeostasis is less understood. Therefore, studies on multicellular model organisms help to decipher how Cdc48-dependent proteolysis is regulated in time and space to meet developmental requirements. Given the importance of developmental regulation and tissue maintenance, defects in Cdc48 activity have been linked to several human pathologies including protein aggregation diseases. Thus, addressing the underlying disease mechanisms not only contributes to our understanding on the organism-wide function of Cdc48 but also facilitates the design of specific medical therapies. In this review, we will portray the role of Cdc48 in the context of multicellular organisms, pointing out its importance for developmental processes, tissue surveillance, and disease prevention. This article is part of a Special Issue entitled: Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.     

Multiple functions of insulin-degrading enzyme: a metabolic crosslight?

Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involvement in the onset of diabetes has been largely investigated. However, further studies on IDE unraveled its ability to degrade several other polypeptides, such as β-amyloid, amylin, and glucagon, envisaging the possible implication of IDE dys-regulation in the “aggregopathies” and, in particular, in neurodegenerative diseases. Over the last decade, a novel scenario on IDE biology has emerged, pointing out a multi-functional role of this enzyme in several basic cellular processes. In particular, latest advances indicate that IDE behaves as a heat shock protein and modulates the ubiquitin–proteasome system, suggesting a major implication in proteins turnover and cell homeostasis. In addition, recent observations have highlighted that the regulation of glucose metabolism by IDE is not merely based on its largely proposed role in the degradation of insulin in vivo. There is increasing evidence that improper IDE function, regulation, or trafficking might contribute to the etiology of metabolic diseases. In addition, the enzymatic activity of IDE is affected by metals levels, thus suggesting a role also in the metal homeostasis (metallostasis), which is thought to be tightly linked to the malfunction of the “quality control” machinery of the cell. Focusing on the physiological role of IDE, we will address a comprehensive vision of the very complex scenario in which IDE takes part, outlining its crucial role in interconnecting several relevant cellular processes.     

Intermediate filaments in cardiomyopathy

Intermediate filament (IF) proteins are critical regulators in health and disease. The discovery of hundreds of mutations in IF genes and posttranslational modifications has been linked to a plethora of human diseases, including, among others, cardiomyopathies, muscular dystrophies, progeria, blistering diseases of the epidermis, and neurodegenerative diseases. The major IF proteins that have been linked to cardiomyopathies and heart failure are the muscle-specific cytoskeletal IF protein desmin and the nuclear IF protein lamin, as a subgroup of the known desminopathies and laminopathies, respectively. The studies so far, both with healthy and diseased heart, have demonstrated the importance of these IF protein networks in intracellular and intercellular integration of structure and function, mechanotransduction and gene activation, cardiomyocyte differentiation and survival, mitochondrial homeostasis, and regulation of metabolism. The high coordination of all these processes is obviously of great importance for the maintenance of proper, life-lasting, and continuous contraction of this highly organized cardiac striated muscle and consequently a healthy heart. In this review, we will cover most known information on the role of IFs in the above processes and how their deficiency or disruption leads to cardiomyopathy and heart failure.     

Parkin:一种作用极其广泛的E3泛素连接酶

Parkin,又名PARK2,自发现初始便与帕金森病(Parkinson's disease,PD)密切相关.Parkin被认为是一种神经保护性基因.随着对其结构的深入了解,揭开了作为E3泛素连接酶的面纱.Parkin参与调控细胞周期、线粒体动态平衡和能量代谢等细胞进程,并与许多疾病息息相关,甚至在同一通路中发挥完全相...     

Apolipoprotein D--an atypical apolipoprotein.

The structure of ApoD and its sites of synthesis have been discovered. These characteristics differ from those of the other apolipoproteins. The role of ApoD in the plasma lipoprotein system remains to be discovered, but the recent, rapid increase in our knowledge of this protein suggests that it plays an important role in the homeostasis or housekeeping of probably all organs. One of its functions is likely to be the transport of a hydrophobic ligand (a lipid) in a one-to-one molar ratio with itself. This transport is likely to occur unidirectionally between neighboring cells in an organ, and between perivascular cells and the blood circulation. The chemical structure of the natural ligand, or ligands, of ApoD in normal cells in vivo or in culture is not known, but ApoD has been shown to bind some steroids and bilirubin. Remarkable upregulation of synthesis of ApoD has been observed during regeneration of injured peripheral nerves. Perhaps the physiologic role of ApoD will prove to be more interesting and of equal importance in biology to the roles of the other apolipoproteins in cardiovascular disease.     

Biochemistry, physiology and pathophysiology of the extracellular calcium-sensing receptor

Calcium (Ca(2+)) has long been recognized as a physiologically indispensable ion owing to its numerous intra- and extracellular roles. More recently, it has become apparent that extracellular calcium (Ca(2+)(o)) also serves as an extracellular first messenger following the cloning of a Ca(2+)(o)-sensing receptor (CaR) that belongs to the superfamily of G protein-coupled receptors (GPCR). The CaR probably functions as a dimer in performing its central role of "sensing" minute alterations in Ca(2+)(o) and adjusting the secretion of parathyroid hormone (PTH) so as to normalize Ca(2+)(o) through the actions of PTH on the effector elements of the mineral ion homeostatic system (e.g., kidney, bone and intestine). Several inherited human conditions are caused by inactivating or activating mutations of this receptor, and mice have been generated with targeted disruption of the CaR gene. Characteristic changes in the functions of parathyroid and kidney in patients with these conditions and in CaR-deficient mice have proven the physiological importance of the CaR in mineral ion homeostasis. An accumulating body of evidence, however, suggests that the CaR also plays numerous roles outside the realm of systemic mineral ion homeostasis. The receptor regulates processes such as cellular proliferation and differentiation, secretion, membrane polarization and apoptosis in a variety of tissues/cells. Finally, the availability of specific "calcimimetic", allosteric CaR activators - which are currently in clinical trials - will probably have therapeutic implications for diseases caused by malfunction of the CaR in tissues not only within, but also outside, the mineral ion homeostatic system.     

胞红蛋白在调控细胞铁死亡中的作用

近年来,以细胞内氧化还原平衡失调为重要诱因,具有铁依赖性和以脂质过氧化物堆积引起细胞膜损伤为主要特征的细胞铁死亡备受关注。越来越多的研究表明,细胞铁死亡在疾病发生及防治方面具有重要作用。胞红蛋白(cytoglobin,CYGB),又名星状细胞激活蛋白 (stellate cell activating protein, STAP),是一种珠蛋白,不仅能可逆地结合氧分子,储存和传递氧气,同时在其氨基酸序列中含2个半胱氨酸残基,可形成分子内部的二硫键,在感受细胞内氧化还原状态变动时,改变自身空间结构,引起生物活性及下游信号通路的变化。同时,CYGB还具有一氧化氮双加氧酶活性,能够清除过量一氧化氮与活性氧物质超氧阴离子反应生成的有毒ONOO^-,防止其对线粒体功能的破坏。而细胞内活氧物质和线粒体是影响细胞铁死亡的重要因素。因此,本综述主要围绕CYGB清除活性氧物质及调控一氧化氮代谢等的作用机制,并结合我们最近有关CYGB通过p53-YAP1轴调控细胞内脂质代谢的研究进行阐述,提出CYGB通过参与细胞铁死亡调控来行使功能,为心血管功能,肝纤维化及癌症发生等相关疾病的预防和治疗提供重要的理论依据。     

Protein misfolding and retinal degeneration

The retina is a highly complex and specialized organ that performs preliminary analysis of visual information. Composed of highly metabolically active tissue, the retina requires a precise and well-balanced means of maintaining its functional activity during extended periods of time. Maintenance and regulation of a vast array of different structural and functional proteins is required for normal function of the retina. This process is referred to as protein homeostasis and involves a variety of activities, including protein synthesis, folding, transport, degradation, elimination, and recycling. Deregulation of any of these activities can lead to malfunctioning of the retina, from subtle subclinical signs to severe retinal degenerative diseases leading to blindness. Examples of retinal degenerative diseases caused by disruption of protein homeostasis include retinitis pigmentosa and Stargardt's disease. A detailed discussion of the role of disruption in protein homeostasis in these and other retinal diseases is presented, followed by examples of some existing and potential treatments.