Yeast as a model for studying human neurodegenerative disorders

Protein misfolding and aggregation are central events in many disorders including several neurodegenerative diseases. This suggests that alterations in normal protein homeostasis may contribute to pathogenesis, but the exact molecular mechanisms involved are still poorly understood. The budding yeast Saccharomyces cerevisiae is one of the model systems of choice for studies in molecular medicine. Modeling human neurodegenerative diseases in this simple organism has already shown the incredible power of yeast to unravel the complex mechanisms and pathways underlying these pathologies. Indeed, this work has led to the identification of several potential therapeutic targets and drugs for many diseases, including the neurodegenerative diseases. Several features associated with these diseases, such as formation of protein aggregates, cellular toxicity mediated by misfolded proteins, oxidative stress and hallmarks of apoptosis have been faithfully recapitulated in yeast, enabling researchers to take advantage of this powerful model to rapidly perform genetic and compound screens with the aim of identifying novel candidate therapeutic targets and drugs. Here we review the work undertaken to model human brain disorders in yeast, and how these models provide insight into novel therapeutic approaches for these diseases.     

Harnessing the power of yeast to unravel the molecular basis of neurodegeneration

Several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or prion diseases, are known for their intimate association with protein misfolding and aggregation. These disorders are characterized by the loss of specific neuronal populations in the brain and are highly associated with aging, suggesting a decline in proteostasis capacity may contribute to pathogenesis. Nevertheless, the precise molecular mechanisms that lead to the selective demise of neurons remain poorly understood. As a consequence, appropriate therapeutic approaches and effective treatments are largely lacking. The development of cellular and animal models that faithfully reproduce central aspects of neurodegeneration has been crucial for advancing our understanding of these diseases. Approaches involving the sequential use of different model systems, starting with simpler cellular models and ending with validation in more complex animal models, resulted in the discovery of promising therapeutic targets and small molecules with therapeutic potential. Within this framework, the simple and well‐characterized eukaryote Saccharomyces cerevisiae, also known as budding yeast, is being increasingly used to study the molecular basis of several neurodegenerative disorders. Yeast provides an unprecedented toolbox for the dissection of complex biological processes and pathways. Here, we summarize how yeast models are adding to our current understanding of several neurodegenerative disorders.     

Age related mitochondrial degenerative disorders in humans

Disorders caused by mitochondrial respiratory chain deficiency due to mutations in mitochondrial DNA have varied phenotypes but many involve neurological features often associated with cell loss within specific brain regions. These disorders, along with the increasing evidence of decline in mitochondrial function with ageing, have raised speculation that primary changes in mitochondria could have an important role in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence supporting a role for mitochondria in common neurodegenerative diseases comes from studies with the toxin MPP+ and familial PD, which has been shown to involve proteins such as DJ-1 and Pink1 (both of which are predicted to have a role in mitochondrial function and oxidative stress). Mutations within the mitochondrial genome have been shown to accumulate with age and in common neurodegenerative diseases. Mitochondrial DNA haplogroups have also been shown to be associated with certain neurodegenerative conditions. This review covers the primary mitochondrial diseases but also discuss the potential role of mitochondria and mitochondrial DNA mutations in mitochondrial and neurodegenerative diseases, in particular in PD and in AD.     

From Alzheimer to Huntington: why is a structural understanding so difficult?

An increasing family of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, prion encephalopathies and cystic fibrosis is associated with aggregation of misfolded polypeptide chains which are toxic to the cell. Knowledge of the three-dimensional structure of the proteins implicated is essential for understanding why and how endogenous proteins may adopt a non-native fold. Yet, structural work has been hampered by the difficulty of handling proteins insoluble or prone to aggregation, and at the same time that is why it is interesting to study these molecules. In this review, we compare the structural knowledge accumulated for two paradigmatic misfolding disorders, Alzheimer's disease (AD) and the family of poly-glutamine diseases (poly-Q) and discuss some of the hypotheses suggested for explaining aggregate formation. While a common mechanism between these pathologies remains to be proven, a direct comparison may help in designing new strategies for approaching their study.     

氧化应激及天然抗氧化剂对阿尔茨海默病的缓解作用（英文）

衰老是阿尔茨海默病（Alzheimer’s disease,AD）等神经退行性疾病的主要危险因素。氧化应激和自由基具有重要的生物学功能,氧化还原失衡导致氧化应激,与包括AD在内的许多人类疾病的病理生理有关。本文综述了活性氧（ROS）参与神经退行性疾病发病的相关机制,特别是氧化应激与AD其他关键机制的相互作用,并总结了茶多酚、L-茶氨酸、虾青素、EGb761、大豆异黄酮和烟碱在细胞和动物模型中对AD的防护作用以及在临床上对相关疾病的缓解作用。希望该综述能为AD的预防和治疗策略提供一些见解。     

The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer's and Parkinson's diseases

Alzheimer's (AD) and Parkinson's diseases (PD) are late-onset neurodegenerative diseases that have tremendous impact on the lives of affected individuals, their families, and society as a whole. Remarkable efforts are being made to elucidate the dominant factors that result in the pathogenesis of these disorders. Extensive postmortem studies suggest that oxidative/nitrative stresses are prominent features of these diseases, and several animal models support this notion. Furthermore, it is likely that protein modifications resulting from oxidative/nitrative damage contribute to the formation of intracytoplasmic inclusions characteristic of each disease. The frequent presentation of both AD and PD in individuals and the co-occurrence of inclusions characteristic of AD and PD in several other neurodegenerative diseases suggests the involvement of a common underlying aberrant process. It can be surmised that oxidative/nitrative stress, which is cooperatively influenced by environmental factors, genetic predisposition, and senescence, may be a link between these disorders.     

Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment

Oxidative stress has been implicated to play a crucial role in the pathogenesis of a number of diseases, including neurodegenerative disorders, cancer, and ischemia, just to name a few. Alzheimer disease (AD) is an age-related neurodegenerative disorder that is recognized as the most common form of dementia. AD is histopathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, the presence of oligomers of amyloid beta-peptide (Abeta), and synapse loss. In this review we discuss the role of Abeta in the pathogenesis of AD and also the use of redox proteomics to identify oxidatively modified brain proteins in AD and mild cognitive impairment. In addition, redox proteomics studies in in vivo models of AD centered around human Abeta(1-42) are discussed.     

Different Pathways to Neurodegeneration

The current issue is dedicated to the studies of neurodegenerative diseases and memory. Molecular mechanisms and mutant genes have already been revealed for many neurodegenerative diseases. However, in many cases the cause of selective death of neurons in different brain regions remains unclear. Genetic predisposition and aging are well established risk factors in many neurodegenerative diseases. A large body of evidence has been obtained that shows an important role of immune factors in the modulation of neurodegenerative processes. The progress in the treatment of neurodegenerative diseases requires new cell models for identification of non-canonical pharmacological targets and development of approaches for memory regulation. Gene therapy technologies based on genome editing and RNA interference methods are among promising approaches for repairing primary molecular defects underlying neurodegenerative pathologies.     

Conditionally inducible tau mice – designing a better mouse model of neurodegenerative diseases

Neuronal cell death underlies the majority of age-related human neurodegenerative disorders that culminate with salient and severe cognitive decline affecting patients' quality of life, identity and eventually leading to death. The identification of disease-causing genes in familial forms of neurodegenerative diseases enabled the development of genetic models closely replicating pathologies found in human central nervous system. These models dramatically precipitated our understanding of molecular events leading to neuronal death in many neurodegenerative disorders. Today's large range of cellular and animal models generate rapidly accumulating biochemical and neuropathological data on changes induced by mutated or dysfunctional proteins implicated in neuronal loss. Most of these models are complementary, although all have intrinsic limitations as well as specific advantages. Development of conditional transgenic mouse models in which a deleterious effect of a transgene can be regulated in a controlled way created new possibilities of addressing the basic mechanisms of neurodegeneration and provided a new angle for the development and testing of new therapeutic approaches.     

Mesenchymal stromal cells (MSCs) for neurodegenerative disease: A promising frontier

Neurodegenerative disorders are a variety of diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) along with some other less common diseases generally described by the advanced deterioration of central or peripheral nervous system, structurally or functionally. In the last two decades, mesenchymal stromal cells (MSCs) due to their unique assets encompassing self-renewal, multipotency and accessibility in association with low ethical concern open new frontiers in the context of neurodegenerative diseases therapy. Interestingly, MSCs can be differentiated into endodermal and ectodermal lineages (e.g., neurons, oligodendrocyte, and astrocyte), and thus could be employed to advance cell-based therapeutic strategy. Additionally, as inflammation ordinarily ensues as a local response provoked by microglia in the neurodegenerative diseases, MSCs therapy because of their pronounced immunomodulatory properties is noticed as a rational approach for their treatment. Recently, varied types of studies have been mostly carried out in vitro and rodent models using MSCs upon their procurement from various sources and expansion. The promising results of the studies in rodent models have motivated researchers to design and perform several clinical trials, with a speedily rising number. In the current review, we aim to deliver a brief overview of MSCs sources, expansion strategies, and their immunosuppressive characteristics and discuss credible functional mechanisms exerted by MSCs to treat neurodegenerative disorders, covering AD, PD, ALS, MS, and HD.     

Cyclodextrins promote protein aggregation posing risks for therapeutic applications

The presence of neurofibrillary tangles (NFTs) is a hallmark feature of various neurodegenerative disorders including Alzheimer’s (AD) and Niemann-Pick type C (NPC) diseases. NFTs have been correlated with elevated cholesterol levels and a cholesterol-scavenging compound, cyclodextrin, effectively modulates and traffics cholesterol from cell bodies in NPC disease models. Cyclodextrins are also used as drug carriers to the blood-brain barrier (BBB) and other tissues. While cyclodextrins have potential value in treating brain diseases, it is important to determine how cyclodextrins affect natively unfolded proteins such as beta-amyloid (Aβ) whose aggregation has been correlated with AD. We show that cyclodextrins drastically alter Aβ aggregation kinetics and induce morphological changes to Aβ that can enhance toxicity towards SH-SY5Y human neuroblastoma cells. These results suggest that care must be taken when using cyclodextrins for BBB delivery or for treatment of brain disease because cyclodextrins can promote toxic aggregation of Aβ.     

The alpha-ketoglutarate dehydrogenase complex in neurodegeneration

Altered energy metabolism is characteristic of many neurodegenerative disorders. Reductions in the key mitochondrial enzyme complex, the alpha-ketoglutarate dehydrogenase complex (KGDHC), occur in a number of neurodegenerative disorders including Alzheimer's Disease (AD). The reductions in KGDHC activity may be responsible for the decreases in brain metabolism, which occur in these disorders. KGDHC can be inactivated by several mechanisms, including the actions of free radicals (Reactive Oxygen Species, ROS). Other studies have associated specific forms of one of the genes encoding KGDHC (namely the DLST gene) with AD, Parkinson's disease, as well as other neurodegenerative diseases. Reductions in KGDHC activity can be plausibly linked to several aspects of brain dysfunction and neuropathology in a number of neurodegenerative diseases. Further studies are needed to assess mechanisms underlying the sensitivity of KGDHC to oxidative stress and the relation of KGDHC deficiency to selective vulnerability in neurodegenerative diseases.     

Modeling human neurodegenerative diseases in transgenic systems

Transgenic systems are widely used to study the cellular and molecular basis of human neurodegenerative diseases. A wide variety of model organisms have been utilized, including bacteria (Escherichia coli), plants (Arabidopsis thaliana), nematodes (Caenorhabditis elegans), arthropods (Drosophila melanogaster), fish (zebrafish, Danio rerio), rodents (mouse, Mus musculus and rat, Rattus norvegicus) as well as non-human primates (rhesus monkey, Macaca mulatta). These transgenic systems have enormous value for understanding the pathophysiological basis of these disorders and have, in some cases, been instrumental in the development of therapeutic approaches to treat these conditions. In this review, we discuss the most commonly used model organisms and the methodologies available for the preparation of transgenic organisms. Moreover, we provide selected examples of the use of these technologies for the preparation of transgenic animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD) and discuss the application of these technologies to AD as an example of how transgenic modeling has affected the study of human neurodegenerative diseases.     

Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders

The common underlying feature of most neurodegenerative diseases such as Alzheimer disease (AD), prion diseases, Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) involves accumulation of misfolded proteins leading to initiation of endoplasmic reticulum (ER) stress and stimulation of the unfolded protein response (UPR). Additionally, ER stress more recently has been implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Autophagy plays an essential role in the clearance of aggregated toxic proteins and degradation of the damaged organelles. There is evidence that autophagy ameliorates ER stress by eliminating accumulated misfolded proteins. Both abnormal UPR and impaired autophagy have been implicated as a causative mechanism in the development of various neurodegenerative diseases. This review highlights recent advances in the field on the role of ER stress and autophagy in AD, prion diseases, PD, ALS and HAND with the involvement of key signaling pathways in these processes and implications for future development of therapeutic strategies.     

Genes and the Environment in Neurodegeneration

Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene–environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and prion diseases.) and discuss possible links of gene–environment interplay including, where implicated, mitochondrial genes.     

The downward spiral of tau and autolysosomes

A growing body of research has connected autophagy to neurodegenerative diseases such as Alzheimer disease (AD). In autopsied AD brain, large multivesicular bodies accumulate in neurons. Knockout mice deficient for key autophagy genes demonstrate age-dependent neurodegeneration. Most neurodegenerative diseases are characterized by accumulation of insoluble protein species; the type of protein and the location of aggregates within the nervous system help to define the type of disorder. It has been hypothesized that the inability to degrade such aggregates is a major causative factor in neuronal dysfunction and eventual neuronal death. As neurons are postmitotic and thus cannot regenerate themselves, mechanisms of protein clearance have received much attention in the field. The function of the ubiquitin-proteasome system (UPS) is impaired in models of neurodegeneration, and overexpression of chaperone proteins, such as those in the HSP70 family, leads to beneficial effects in many models of proteinopathies. Recently, studies of the effects of autophagy as a clearance mechanism have uncovered compelling evidence that inducing autophagy can alleviate many pathogenic and behavioral symptoms in animal and cellular models of neurodegeneration.     

The downward spiral of tau and autolysosomes: A new hypothesis in neurodegeneration

A growing body of research has connected autophagy to neurodegenerative diseases such as Alzheimer disease (AD). In autopsied AD brain, large multivesicular bodies accumulate in neurons. Knockout mice deficient for key autophagy genes demonstrate age-dependent neurodegeneration. Most neurodegenerative diseases are characterized by accumulation of insoluble protein species; the type of protein and the location of aggregates within the nervous system help to define the type of disorder. It has been hypothesized that the inability to degrade such aggregates is a major causative factor in neuronal dysfunction and eventual neuronal death. As neurons are postmitotic and thus cannot regenerate themselves, mechanisms of protein clearance have received much attention in the field. The function of the ubiquitin-proteasome system (UPS) is impaired in models of neurodegeneration, and overexpression of chaperone proteins, such as those in the HSP70 family, leads to beneficial effects in many models of proteinopathies. Recently, studies of the effects of autophagy as a clearance mechanism have uncovered compelling evidence that inducing autophagy can alleviate many pathogenic and behavioral symptoms in animal and cellular models of neurodegeneration.     

The α-ketoglutarate-dehydrogenase complex

Damage from oxidative stress and mitochondrial dysfunction occur together in many common neurodegenerative diseases. The enzymes that form the mitochondrial alpha-ketoglutarate- dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. KGDHC activity is reduced in numerous age-related neurodegenerative diseases and is diminished by oxidative stress. In Alzheimer's disease (AD), the reduction correlates highly to diminished mental performance. Thus, research has focused on the mechanisms by which select oxidants reduce KGDHC and the consequences of such a reduction. Diminished KGDHC in cells is associated with apoptosis without changes in the mitochondrial membrane potential. Studies of isolated mitochondria and of animal models suggest that a reduction in KGDHC can predispose to damage by other toxins that promote neurodegeneration. Diminished oxidative metabolism can be plausibly linked to pathological features of neurodegenerative diseases (e.g., reduced mental function, the plaques and tangles in AD). Thus, reductions in KGDHC might be central to the pathophysiology of these diseases. Studies of proteins, cells, animal models, and humans suggest that treatments to diminish, or bypass, the reduction in KGDHC might be beneficial in age-related neurodegenerative disorders.     

Role of Sirt1 During the Ageing Process: Relevance to Protection of Synapses in the Brain

Ageing is a stochastic process associated with a progressive decline in physiological functions which predispose to the pathogenesis of several neurodegenerative diseases. The intrinsic complexity of ageing remains a significant challenge to understand the cause of this natural phenomenon. At the molecular level, ageing is thought to be characterized by the accumulation of chronic oxidative damage to lipids, proteins and nucleic acids caused by free radicals. Increased oxidative stress and misfolded protein formations, combined with impaired compensatory mechanisms, may promote neurodegenerative disorders with age. Nutritional modulation through calorie restriction has been shown to be effective as an anti-ageing factor, promoting longevity and protecting against neurodegenerative pathology in yeast, nematodes and murine models. Calorie restriction increases the intracellular levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD⁺), a co-substrate for the sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1) activity and a cofactor for oxidative phosphorylation and ATP synthesis. Promotion of intracellular NAD⁺ anabolism is speculated to induce neuroprotective effects against amyloid-β-peptide (Aβ) toxicity in some models for Alzheimer’s disease (AD). The NAD⁺-dependent histone deacetylase, Sirt1, has been implicated in the ageing process. Sirt1 serves as a deacetylase for numerous proteins involved in several cellular pathways, including stress response and apoptosis, and plays a protective role in neurodegenerative disorders, such as AD.     

Alzheimer's and Parkinson's disease--overlapping or synergistic pathologies?

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders in humans. They are characterized by insoluble protein deposits; beta-amyloid plaques and tau-containing neurofibrillary lesions in AD, and alpha-synuclein-containing Lewy bodies in PD. As a significant percentage of patients have clinical and pathological features of both diseases, the patho-cascades of the two diseases might overlap. For the first time, new animal models that express multiple transgenes provide the tools to dissect the pathogenic pathways and to differentiate between additive and synergistic effects.