阿尔茨海默病转基因小鼠的特点和应用

建立动物模型的目的是在实验动物身上复制人类疾病的模型,用于研究人类疾病的病因、发病、病理变化以及疾病的预防和治疗。目前尚无理想的阿尔茨海默病（Alzheimer’s disease,AD）动物模型,AD实验动物模型的滞后在很大程度上制约了AD治疗药物的筛选。随着AD病因和发病机制研究的不断深入,更完善的AD动物模型也在陆续出现。近年来出现的转基因动物模型属于AD的病因模型,但也不能完整复制出AD的所有特征。最大的缺憾在于缺乏神经原纤维缠结（neurofibrillary tangles,NFTs）和在某些转基因模型中（尤其是单转基因模型）无广泛的神经元丢失。虽然用免疫组化方法检测到tau蛋白,但从未发现成对螺旋纤丝（paired helical filaments,PHF）。     

Influence of species differences on the neuropathology of transgenic Huntington's disease animal models

Transgenic animal models have revealed much about the pathogenesis of age-dependent neurodegenerative diseases and proved to be a useful tool for uncovering therapeutic targets.Huntington's disease is ...     

Small rodent models of hepatitis B and C virus replication and pathogenesis

The narrow host range of infection supporting the long-term propagation of hepatitis B and C viruses is a major limitation that has prevented a more thorough understanding of persistent infection and t...     

Synphilin suppresses α-synuclein neurotoxicity in a Parkinson's disease Drosophila model

Parkinson's disease (PD) is the second most common neurodegenerative disorder in humans. It affects 1% of the population over 65-years old. Its causes are environmental and genetic. As the world population ages, there is an urgent need for better and more detailed animal models for this kind of disease. In this work we show that the use of transgenic Drosophila is comparable to more complicated and costly animal models such as mice. The Drosophila model behaves very similar to the equivalent transgenic mice model. We show that both Synphilin-1 and α-synuclein are toxic by themselves, but when co-expressed, they suppress their toxicity reciprocally. Importantly, the symptoms induced in the fly can be treated and partially reverted using standard PD pharmacological treatments. This work showcases Drosophila as a detailed and multifaceted model for Parkinson's disease, providing a convenient platform in which to study and find new genetic modifiers of PD. genesis 49:392-402, 2011.     

Transgenic nonhuman primates for neurodegenerative diseases

Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD), Parkinson's disease (PD) and Huntington's disease (HD) have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP) has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage) will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which genetic disorders play in the development of efficacious interventions and medications is foreseeable.     

Genetically Modified Pig Models for Human Diseases

Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies.Although genetically modified mice have been widely used to model human diseases,some of these mouse models do not replicate important disease symptoms or pathology.Pigs are more similar to humans than mice in anatomy,physiology,and genome. Thus,pigs are considered to be better animal models to mimic some human diseases.This review describes genetically modified pigs that have been used to model various diseases including neurological,cardiovascular,and diabetic disorders.We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.     

帕金森病动物模型:揭开人类帕金森病奥秘的钥匙

帕金森病（Parkinson‘s disease,PD)是一种以黑质致密部多巴胺能神经元的特异性,进行性坏死为特征的神经系统退行性疾病,尽管PD的发病原因还不十分清楚,目前的证据表明环境因素和遗传因素是PD可能的主要致病因素,针对这两大因素,神经科学家们发展了很多制造PD动物模型的方法,MPTP（1-甲基-4-氨基-1,2,3,6-四氢吡啶）模型是目前比较经典的模型。而新近兴起的基因工程模型亦具有广阔的应用前景咯种PD动物模型推动着人们对PD认识的深入和治疗手段的发展,恰当的动物模型必将成为最终揭开人类帕金森病奥秘的钥匙。     

Ubiquitin-proteasome system dysfunction in Parkinson's disease: current evidence and controversies

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Although a subject of intense research, the etiology of PD remains poorly understood. Over the last decade, the ubiquitin-proteasome system (UPS) has emerged as a compelling player in PD pathogenesis. Disruption of the UPS, which normally identifies and degrades intracellular proteins, is thought to promote the toxic accumulation of proteins detrimental to neuronal survival, thereby contributing to their demise. Support for this came from a broad range of studies, including genetics, gene profiling and post-mortem analysis, as well as in vitro and in vivo modeling. Notably, various cellular and animal models of PD based on direct disruption of UPS function reproduce the salient features of PD. However, several gaps remain in our current knowledge regarding the precise role of UPS dysfunction in the pathogenesis of the disease. Current thoughts regarding their relationship are reviewed here and some major unresolved questions, the clarification of which would considerably advance our understanding of the implicated role of the UPS in PD pathogenesis, are discussed.     

Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinsons disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common classical toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.g. rotenone, paraquat, maneb) are discussed elsewhere in this special issue.This work was supported by grants from the Deutsche Forschungsgemeinschaft.     

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.     

Ubiquitin–proteasome system dysfunction in Parkinson’s disease: current evidence and controversies

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Although a subject of intense research, the etiology of PD remains poorly understood. Over the last decade, the ubiquitin–proteasome system (UPS) has emerged as a compelling player in PD pathogenesis. Disruption of the UPS, which normally identifies and degrades intracellular proteins, is thought to promote the toxic accumulation of proteins detrimental to neuronal survival, thereby contributing to their demise. Support for this came from a broad range of studies, including genetics, gene profiling and post-mortem analysis, as well as in vitro and in vivo modeling. Notably, various cellular and animal models of PD based on direct disruption of UPS function reproduce the salient features of PD. However, several gaps remain in our current knowledge regarding the precise role of UPS dysfunction in the pathogenesis of the disease. Current thoughts regarding their relationship are reviewed here and some major unresolved questions, the clarification of which would considerably advance our understanding of the implicated role of the UPS in PD pathogenesis, are discussed.     

Evaluation of TorsinA as a Target for Parkinson Disease Therapy in Mouse Models

Parkinson disease (PD) is a common and disabling disorder. No current therapy can slow or reverse disease progression. An important aspect of research in this field is target validation, a systematic approach to evaluating the likelihood that modification of a certain molecule, mechanism or biological pathway may be useful for the development of pharmacological or molecular treatments for the disease. TorsinA, a member of the AAA+ family of chaperone proteins, has been proposed as a potential target of neuroprotective therapy. TorsinA is found in Lewy bodies in human PD, and can suppress toxicity in cellular and invertebrate models of PD. Here, we evaluated the neuroprotective properties of torsinA in mouse models of PD based on intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as recombinant adeno associated virus (rAAV) induced overexpression of alpha-synuclein (α-syn). Using either transgenic mice with overexpression of human torsinA (hWT mice) or mice in which torsinA expression was induced using an rAAV vector, we found no evidence for protection against acute MPTP intoxication. Similarly, genetic deletion of the endogenous mouse gene for torsinA (Dyt1) using an rAAV delivered Cre recombinase did not enhance the vulnerability of dopaminergic neurons to MPTP. Overexpression of α-syn using rAAV in the mouse substantia nigra lead to a loss of TH positive neurons six months after administration, and no difference in the degree of loss was observed between transgenic animals expressing forms of torsinA and wild type controls. Collectively, we did not observe evidence for a protective effect of torsinA in the mouse models we examined. Each of these models has limitations, and there is no single model with established predictive value with respect to the human disease. Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD.     

Omega-3 fatty acids in neurodegenerative diseases: Focus on mitochondria

Mitochondrial dysfunction represents a common early pathological event in brain aging and in neurodegenerative diseases, e.g., in Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s disease (HD), as well as in ischemic stroke. In vivo and ex vivo experiments using animal models of aging and AD, PD, and HD mainly showed improvement of mitochondrial function after treatment with polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA). Thereby, PUFA are particular beneficial in animals treated with mitochondria targeting toxins. However, DHA showed adverse effects in a transgenic PD mouse model and it is not clear if a diet high or low in PUFA might provide neuroprotective effects in PD. Post-treatment with PUFA revealed conflicting results in ischemic animal models, but intravenous administered DHA provided neuroprotective efficacy after acute occlusion of the middle cerebral artery. In summary, the majority of preclinical data indicate beneficial effects of n-3 PUFA in neurodegenerative diseases, whereas most controlled clinical trials did not meet the expectations. Because of the high half-life of DHA in the human brain clinical studies may have to be initiated much earlier and have to last much longer to be more efficacious.     

Mitochondrial Dysfunction and Oxidative Stress in Parkinson’s Disease

Environmental toxins, genetic predisposition and old age are major risk factors for Parkinson’s disease (PD). Although the mechanism(s) underlying selective dopaminergic (DA) neurodegeneration remain unclear, molecular studies in both toxin based models and genetic based models of the disease suggest a major etiologic role for mitochondrial dysfunction in the pathogenesis of PD. Further, recent studies have presented clear evidence for a high burden of mtDNA deletions within the substantia nigra neurons in individuals with PD. Ultimately, an understanding of the molecular events which precipitate DA neurodegeneration in idiopathic PD will enable the development of targeted and effective therapeutic strategies. We review recent advances and current understanding of the genetic factors, molecular mechanisms and animal models of PD.     

Unaltered Striatal Dopamine Release Levels in Young Parkin Knockout,Pink1 Knockout,DJ-1 Knockout and LRRK2 R1441G Transgenic Mice

Parkinson''s disease (PD) is one of the most prevalent neurodegenerative brain diseases; it is accompanied by extensive loss of dopamine (DA) neurons of the substantia nigra that project to the putamen, leading to impaired motor functions. Several genes have been associated with hereditary forms of the disease and transgenic mice have been developed by a number of groups to produce animal models of PD and to explore the basic functions of these genes. Surprisingly, most of the various mouse lines generated such as Parkin KO, Pink1 KO, DJ-1 KO and LRRK2 transgenic have been reported to lack degeneration of nigral DA neuron, one of the hallmarks of PD. However, modest impairments of motor behavior have been reported, suggesting the possibility that the models recapitulate at least some of the early stages of PD, including early dysfunction of DA axon terminals. To further evaluate this possibility, here we provide for the first time a systematic comparison of DA release in four different mouse lines, examined at a young age range, prior to potential age-dependent compensations. Using fast scan cyclic voltammetry in striatal sections prepared from young, 6–8 weeks old mice, we examined sub-second DA overflow evoked by single pulses and action potential trains. Unexpectedly, none of the models displayed any dysfunction of DA overflow or reuptake. These results, compatible with the lack of DA neuron loss in these models, suggest that molecular dysfunctions caused by the absence or mutation of these individual genes are not sufficient to perturb the function and survival of mouse DA neurons.     

Modeling sarcomagenesis using multipotent mesenchymal stem cells

Because of their unique properties, multipotent mesenchymal stem cells (MSCs) represent one of the most promising adult stem cells being used worldwide in a wide array of clinical applications. Overall, compelling evidence supports the long-term safety of ex vivo expanded human MSCs, which do not seem to transform spontaneously. However, experimental data reveal a link between MSCs and cancer, and MSCs have been reported to inhibit or promote tumor growth depending on yet undefined conditions. Interestingly, solid evidence based on transgenic mice and genetic intervention of MSCs has placed these cells as the most likely cell of origin for certain sarcomas. This research area is being increasingly explored to develop accurate MSC-based models of sarcomagenesis, which will be undoubtedly valuable in providing a better understanding about the etiology and pathogenesis of mesenchymal cancer, eventually leading to the development of more specific therapies directed against the sarcoma-initiating cell. Unfortunately, still little is known about the mechanisms underlying MSC transformation and further studies are required to develop bona fide sarcoma models based on human MSCs. Here, we comprehensively review the existing MSC-based models of sarcoma and discuss the most common mechanisms leading to tumoral transformation of MSCs and sarcomagenesis.     

α-synuclein致病机制和转基因帕金森疾病模型研究进展

α-synuclein是一种位于突触前末梢的蛋白,是遗传性和散发性帕金森病的特征性包涵体———路易小体的主要成分。α-synuclein基因突变或者遗传改变可导致帕金森病。大量研究揭示α-synuclein参与了神经元的变性过程。本文对α-synuclein在帕金森疾病中的神经元毒性机制以及α-synuclein转基因帕金森病动物模型研究进展进行了综述。     

Genetic models of Parkinson disease

To date, a truly representative animal model of Parkinson disease (PD) remains a critical unmet need. Although toxin-induced PD models have served many useful purposes, they have generally failed to recapitulate accurately the progressive process as well as the nature and distribution of the human pathology. During the last decade or so, the identification of several genes whose mutations are causative of rare familial forms of PD has heralded in a new dawn for PD modelling. Numerous mammalian as well as non mammalian models of genetically-linked PD have since been created. However, despite initial optimism, none of these models turned out to be a perfect replica of PD. Meanwhile, genetic and toxin-induced models alike continue to evolve towards mimicking the disease more faithfully. Notwithstanding this, current genetic models have collectively illuminated several important pathways relevant to PD pathogenesis. Here, we have attempted to provide a comprehensive discussion on existing genetic models of PD.