TRIM family proteins: roles in proteostasis and neurodegenerative diseases

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer''s disease (AD), Parkinson''s disease (PD) and Huntington''s disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs.     

Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes

Background

Genome-wide association studies (gwas) are invaluable in revealing the common variants predisposing to complex human diseases. Yet, until now, the large volumes of data generated from such analyses have not been explored extensively enough to identify the molecular and functional framework hosting the susceptibility genes.

Methodology/Principal Findings

We investigated the relationships among five neurodegenerative and/or autoimmune complex human diseases (Parkinson''s disease-Park, Alzheimer''s disease-Alz, multiple sclerosis-MS, rheumatoid arthritis-RA and Type 1 diabetes-T1D) by characterising the interactomes linked to their gwas-genes. An initial study on the MS interactome indicated that several genes predisposing to the other autoimmune or neurodegenerative disorders may come into contact with it, suggesting that susceptibility to distinct diseases may converge towards common molecular and biological networks. In order to test this hypothesis, we performed pathway enrichment analyses on each disease interactome independently. Several issues related to immune function and growth factor signalling pathways appeared in all autoimmune diseases, and, surprisingly, in Alzheimer''s disease. Furthermore, the paired analyses of disease interactomes revealed significant molecular and functional relatedness among autoimmune diseases, and, unexpectedly, between T1D and Alz.

Conclusions/Significance

The systems biology approach highlighted several known pathogenic processes, indicating that changes in these functions might be driven or sustained by the framework linked to genetic susceptibility. Moreover, the comparative analyses among the five genetic interactomes revealed unexpected genetic relationships, which await further biological validation. Overall, this study outlines the potential of systems biology to uncover links between genetics and pathogenesis of complex human disorders.     

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer''s disease, but its effects in Parkinson''s disease (PD) pathogenesis are less understood. Gene-environment interaction models have utility in unmasking the impact of specific cellular pathways in toxicity that may not be observed using a solely genetic or toxicant disease model alone. To evaluate if distinct LOX isozymes selectively contribute to PD-related neurodegeneration, transgenic (i.e. 5-LOX and 12/15-LOX deficient) mice can be challenged with a toxin that mimics cell injury and death in the disorder. Here we describe the use of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a nigrostriatal lesion to elucidate the distinct contributions of LOX isozymes to neurodegeneration related to PD. The use of MPTP in mouse, and nonhuman primate, is well-established to recapitulate the nigrostriatal damage in PD. The extent of MPTP-induced lesioning is measured by HPLC analysis of dopamine and its metabolites and semi-quantitative Western blot analysis of striatum for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine. To assess inflammatory markers, which may demonstrate LOX isozyme-selective sensitivity, glial fibrillary acidic protein (GFAP) and Iba-1 immunohistochemistry are performed on brain sections containing substantia nigra, and GFAP Western blot analysis is performed on striatal homogenates. This experimental approach can provide novel insights into gene-environment interactions underlying nigrostriatal degeneration and PD.     

Thematic Review Series: Bile Acids: Bile acids: regulation of apoptosis by ursodeoxycholic acid

Bile acids are a group of molecular species of acidic steroids with peculiar physical-chemical and biological characteristics. At high concentrations they become toxic to mammalian cells, and their presence is pertinent in the pathogenesis of several liver diseases and colon cancer. Bile acid cytoxicity has been related to membrane damage, but also to nondetergent effects, such as oxidative stress and apoptosis. Strikingly, hydrophilic ursodeoxycholic acid (UDCA), and its taurine-conjugated form (TUDCA), show profound cytoprotective properties. Indeed, these molecules have been described as potent inhibitors of classic pathways of apoptosis, although their precise mode of action remains to be clarified. UDCA, originally used for cholesterol gallstone dissolution, is currently considered the first choice therapy for several forms of cholestatic syndromes. However, the beneficial effects of both UDCA and TUDCA have been tested in other experimental pathological conditions with deregulated levels of apoptosis, including neurological disorders, such as Alzheimer''s, Parkinson''s, and Huntington''s diseases. Here, we review the role of bile acids in modulating the apoptosis process, emphasizing the anti-apoptotic effects of UDCA and TUDCA, as well as their potential use as novel and alternate therapeutic agents for the treatment of apoptosis-related diseases.     

Paraoxonase 1 in neurological disorders

Abstract

Paroxonase 1 displays multiple physiological activities that position it as a putative player in the pathogenesis of neurological disorders. Here we reviewed the literature focusing on the role of paraoxonase 1 (PON1) as a factor in the risk of stroke and the major neurodegenerative diseases. PON1 activity is reduced in stroke patients, which significantly correlates inversely with carotid and cerebral atherosclerosis. The presence of the R allele of the Q192R PON1 polymorphism seems to potentiate this risk for stroke. PON1 exerts peroxidase activities that may be important in neurodegenerative disorders associated with oxidative stress. PON1 is also a key detoxifier of organophosphates and organophosphate exposure has been linked to the development of neurological disorders in which acetylcholine plays a significant role. In Parkinson's disease most of the studies suggest no participation of either L55M or the Q192R polymorphisms in its pathogenesis. However, many studies suggest that the MM55 PON1 genotype is associated with a higher risk for Parkinson's disease in individuals exposed to organophosphates. In Alzheimer's disease most studies have failed to find any association between PON1 polymorphisms and the development of the disease. Some studies show that PON1 activity is decreased in patients with Alzheimer's disease or other dementias, suggesting a possible protective role of PON1. No links between PON1 polymorphisms or activity have been found in other neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis. PON1 is a potential player in the pathogenesis of several neurological disorders. More research is warranted to ascertain the precise pathogenic links and the prognostic value of its measurement in neurological patients.     

The microRNAs (miRs) overexpressing mesenchymal stem cells (MSCs) therapy in neurological disorders; hope or hype

Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. One of the biggest concerns within gene-based therapy is the delivery of the therapeutic microRNAs to the intended place, which is obligated to surpass the biological barriers without undergoing degradation in the bloodstream or renal excretion. Hence, the delivery of modified and unmodified miRNA molecules using excellent vehicles is required. In this light, mesenchymal stem cells (MSCs) have attracted increasing attention. The MSCs can be genetically modified to express or overexpress a particular microRNA aimed with promote neurogenesis and neuroprotection. The current review has focused on the therapeutic capabilities of microRNAs-overexpressing MSCs to ameliorate functional deficits in neurological conditions.     

Animal models for Alzheimer's disease and frontotemporal dementia: a perspective

In dementia research, animal models have become indispensable tools. They not only model aspects of the human condition, but also simulate processes that occur in humans and hence provide insight into how disease is initiated and propagated. The present review discusses two prominent human neurodegenerative disorders, Alzheimer''s disease and frontotemporal dementia. It discusses what we would like to model in animals and highlights some of the more recent achievements using species as diverse as mice, fish, flies and worms. Advances in imaging and therapy are explored. We also discuss some anticipated new models and developments. These will reveal how key players in the pathogenesis of Alzheimer''s disease and frontotemporal dementia, such as the peptide Aβ (amyloid β) and the protein tau, cause neuronal dysfunction and eventually, neuronal demise. Understanding these processes fully will lead to early diagnosis and therapy.     

Genetic Variants in Diseases of the Extrapyramidal System

Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagno-sis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson’s or Huntington’s. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich’s disease, ataxia with ocu-lomotorapraxia, Huntington''s disease, dystonia type 1, Wilson’s disease, and some cases of Parkinson''s disease.     

脑能量代谢与线粒体功能关系的研究进展

线粒体是人体内的能量代谢工厂,而脑是人体内能量代谢最活跃的部位。神经元和胶质细胞是脑内主要的细胞。本文对线粒体在能量产生的作用进行综述,同时比较神经元和星形胶质细胞能量代谢的异同及密切联系,并对神经退行性变中能量代谢障碍与线粒体可塑性改变进行了回顾。以三种神经退行性疾病帕金森、阿尔兹海默和脊髓侧索硬化症为例说明线粒体在神经系统疾病和脑能量代谢之间的重要作用。从而进一步系统的认识,脑内的线粒体在生理和病理状态下对能量代谢的影响。深入了解其机制,为研究神经系统退行性疾病提供新的治疗策略。     

From Kuru to Alzheimer: A personal outlook

Seventy years ago, we learned from Chris Anfinsen that the stereochemical code necessary to fold a protein is embedded into its amino acid sequence. In water, protein morphogenesis is a spontaneous reversible process leading from an ensemble of disordered structures to the ordered functionally competent protein; conforming to Aristotle''s definition of substance, the synolon of matter and form. The overall process of folding is generally consistent with a two state transition between the native and the denatured protein: not only the denatured state is an ensemble of several structures, but also the native protein populates distinct functionally relevant conformational (sub)states. This two‐state view should be revised, given that any globular protein can populate a peculiar third state called amyloid, characterized by an overall architecture that at variance with the native state, is by‐and‐large independent of the primary structure. In a nut shell, we should accept that beside the folded and unfolded states, any protein can populate a third state called amyloid which gained center stage being the hallmark of incurable neurodegenerative disorders, such as Alzheimer''s and Parkinson''s diseases as well as others. These fatal diseases are characterized by clear‐cut clinical differences, yet display some commonalities such as the presence in the brain of amyloid deposits constituted by one misfolded protein specific for each disease. Some aspects of this complex problem are summarized here as an excursus from the prion''s fibrils observed in the brain of aborigines who died of Kuru to the amyloid detectable in the cortex of Alzheimer''s patients.     

An Effective Method to Identify Shared Pathways and Common Factors among Neurodegenerative Diseases

Groups of distinct but related diseases often share common symptoms, which suggest likely overlaps in underlying pathogenic mechanisms. Identifying the shared pathways and common factors among those disorders can be expected to deepen our understanding for them and help designing new treatment strategies effected on those diseases. Neurodegeneration diseases, including Alzheimer''s disease (AD), Parkinson''s disease (PD) and Huntington''s disease (HD), were taken as a case study in this research. Reported susceptibility genes for AD, PD and HD were collected and human protein-protein interaction network (hPPIN) was used to identify biological pathways related to neurodegeneration. 81 KEGG pathways were found to be correlated with neurodegenerative disorders. 36 out of the 81 are human disease pathways, and the remaining ones are involved in miscellaneous human functional pathways. Cancers and infectious diseases are two major subclasses within the disease group. Apoptosis is one of the most significant functional pathways. Most of those pathways found here are actually consistent with prior knowledge of neurodegenerative diseases except two cell communication pathways: adherens and tight junctions. Gene expression analysis showed a high probability that the two pathways were related to neurodegenerative diseases. A combination of common susceptibility genes and hPPIN is an effective method to study shared pathways involved in a group of closely related disorders. Common modules, which might play a bridging role in linking neurodegenerative disorders and the enriched pathways, were identified by clustering analysis. The identified shared pathways and common modules can be expected to yield clues for effective target discovery efforts on neurodegeneration.     

NAD/NADP及其介导氧化应激在神经退行性疾病中的作用

神经退行性疾病如阿尔茨海默病、帕金森病、亨廷顿病等疾病的发生与氧化应激紧密相关。NAD和NADP是维持氧化系统和抗氧化系统平衡的两个关键物质。NAD和NADP的生物合成和降解有多种途径,参与其生物途径的物质如NAMPT、NADK、PARP1、SIRT1、CD38等,均报道在神经退行性疾病发挥一定的作用。因此,本文分别从NAD和NADP的合成和降解途径中的一些关键物质出发,结合氧化应激总结并探讨它们在神经退行性疾病的作用,以期为临床治疗神经退行性疾病提供新思路。     

Genetic connections between neurological disorders and cholesterol metabolism

Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington''s disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer''s disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders.     

Osteoporosis in neurodegeneration

Osteoporosis affects bone microarchitecture and reduces bone mass. There are more than 200 million people with osteoporosis worldwide, and the prevalence is slowly increasing. The highest prevalences are found in Scandinavia and USA, also slowly increasing. A parallel increase in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis has been noted since the middle of this century. Osteoporosis is more common in patients with each of these neurodegenerative conditions than in the general population. Several metals with neurotoxic properties accumulate in bone and can substitute for calcium in hydroxyapatite, the main mineral component of bone. Especially cadmium, but also lead, aluminum and arsenic affect bone mineral density negatively. Metals with neurotoxic properties have also been found in brain and cerebrospinal fluid from patients with Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis, and markers for neurodegeneration such as amyloid beta peptide and amyloid precursor protein have been detected in bone tissue from patients with osteoporosis. A common mechanism contributing to the pathogenesis of both neurodegeneration and osteoporosis can be suspected. The hypothesis that neurodegenerative disorders are associated with osteoporosis is presented and discussed.     

Glutamate,Glutamate Receptors,and Downstream Signaling Pathways

Glutamate is a nonessential amino acid, a major bioenergetic substrate for proliferating normal and neoplastic cells, and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways. Glutamate signaling activates a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in chronic disabling brain disorders such as Schizophrenia and neurodegenerative diseases like Alzheimer''s, Parkinson''s, and multiple sclerosis. In this review, we discuss the structural and functional relationship of mGluRs and iGluRs and their downstream signaling pathways. The three groups of mGluRs, the associated second messenger systems, and subsequent activation of PI3K/Akt, MAPK, NFkB, PLC, and Ca/CaM signaling systems will be discussed in detail. The current state of human mGluR1a as one of the most important isoforms of Group I-mGluRs will be highlighted. The lack of studies on the human orthologues of mGluRs family will be outlined. We conclude that upon further study, human glutamate-initiated signaling pathways may provide novel therapeutic opportunities for a variety of non-malignant and malignant human diseases.     

Parkinson's disease and Alzheimer's disease as disorders of the isodendritic core.

Parkinson''s disease and Alzheimer''s disease may represent two parts of a spectrum of disease characterised by a primary loss of cells of the isodendritic core. Secondary cell loss from the striatum and cerebral cortex therefore occurs as a consequence of the loss of ascending projections from the isodendritic cells. The anatomy of this system should provide a unique opportunity for therapeutic intervention. Neurotransmitter replacement treatment may be provided either by enhancing transmitter release by any remaining neurones or by direct agonists. The wide dispersal of the isodendritic projection systems affected in Parkinson''s and Alzheimer''s disease and the possibility that they are tonically active create an opportunity for neurotransmitter replacement treatment. Animal studies should be able to show whether such treatment can delay secondary cell loss, and, together with human postmortem studies, whether the hypothesis that the primary lesion is a loss of isodendritic cells is correct.