Behavioral testing regimens in genetic-based animal models of Parkinson's disease: Cogencies and caveats (original) (raw)

Animal Models of Autosomal Recessive Parkinsonism

Biomedicines

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. The neuropathological hallmark of the disease is the loss of dopamine neurons of the substantia nigra pars compacta. The clinical manifestations of PD are bradykinesia, rigidity, resting tremors and postural instability. PD patients often display non-motor symptoms such as depression, anxiety, weakness, sleep disturbances and cognitive disorders. Although, in 90% of cases, PD has a sporadic onset of unknown etiology, highly penetrant rare genetic mutations in many genes have been linked with typical familial PD. Understanding the mechanisms behind the DA neuron death in these Mendelian forms may help to illuminate the pathogenesis of DA neuron degeneration in the more common forms of PD. A key step in the identification of the molecular pathways underlying DA neuron death, and in the development of therapeutic strategies, is the creation and characterization of animal models that faithfully recapitulate...

Genetic mouse models of parkinsonism: Strengths and limitations

Neurorx, 2005

Summary Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Patients with PD display a combination of motor symptoms including resting tremor, rigidity, bradykinesia, and postural instability that worsen over time. These motor symptoms are related to the progressive loss of dopamine neurons in the substantia nigra pars compacta. PD patients also suffer from nonmotor symptoms that may precede the cardinal motor

Genetic Rat Models of Parkinson's Disease

Parkinson's Disease, 2012

Parkinson's disease (PD) is a neurodegenerative disease characterized by a specific loss of dopaminergic neurons. Although the vast majority of PD cases are idiopathic in nature, there is a subset that contains genetic links. Of the genes that have been linked to PD, α-synuclein and leucine-rich repeat kinase 2 have been used to develop transgenic rat models of the disease. In this paper we focused on the various transgenic rat models of PD in terms of their ability to mimic key symptoms of PD in a progressive manner. In general, we found that most of these models provided useful tools for the early stages of PD, but the development of new transgenic rats that present significant neuropathologic and motoric deficits in a progressive manner that more accurately mimics PD is needed.

Animal models of Parkinson's disease: vertebrate genetics

Cold Spring Harbor perspectives in medicine, 2012

Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current P...

Genetic mouse models of Parkinson's disease The state of the art

Progress in brain research

The identification of several mutations causing familial forms of Parkinson's disease (PD) has led to the creation of multiple lines of mice expressing similar genetic alterations. These models present a unique opportunity for understanding pathophysiological mechanisms leading to PD in a mammalian brain and provide models that are suitable for the preclinical testing of new therapies. Different lines of mice recapitulate the symptoms and pathological features of PD to various extents. This chapter examines their respective advantages and highlights some of the key findings that have already emerged from the analysis of these new models of PD.

Rodent models of Parkinson's disease: beyond the motor symptomatology

Frontiers in Behavioral Neuroscience, 2013

Parkinson's disease (PD) is classically characterized by motor symptoms; however, non-motor symptoms (NMS) are increasingly recognized as relevant in disease-state, given the associated alterations in mood (depression and anxiety) and cognition. Here, particularly in regards to NMS, we aimed to compare the motor, emotional and cognitive behavior of three animal models of PD that trigger dopaminergic (DAergic) degeneration on both brain hemispheres: (i) the 6-hydroxydopamine (6-OHDA, 8 or 6 μg) lesion model; (ii) the paraquat (PQ) induced model, and (iii) a genetic model based on α-synuclein overexpression (α-syn). 6-OHDA and α-syn vector were injected bilaterally in the substantia nigra pars compacta (SNpc) of adult male Wistar rats; as for PQ delivery, micro-osmotic pumps were implanted in the interscapular region. Motor deficits were observed in all models, with histological analysis of tyrosine hydroxylase positive cells in the SNpc revealing a significant loss of DAergic neurons in all animal models. In addition, the αsyn animal model also presented a reduction in exploratory activity, and the 6-OHDA and PQ animals displayed a significant increase in both depressive-and anxiety-like behavior. Interestingly, cognitive impairment (working memory) was only observed in the 6-OHDA model. Overall, these PD models are suitable for mimicking the motor symptoms associated to PD, with each encompassing other relevant NMS components of the disorder that may prove beneficial for further studies in PD.

A Novel, Sensitive Assay for Behavioral Defects in Parkinson's Disease ModelDrosophila

Parkinson's Disease, 2012

Parkinson's disease is a common neurodegenerative disorder with the pathology ofα-synuclein aggregation in Lewy bodies. Currently, there is no available therapy that arrests the progression of the disease. Therefore, the need of animal models to followα-synuclein aggregation is crucial.Drosophila melanogasterhas been researched extensively as a good genetic model for the disease, with a cognitive phenotype of defective climbing ability. The assay for climbing ability has been demonstrated as an effective tool for screening new therapeutic agents for Parkinson's disease. However, due to the assay's many limitations, there is a clear need to develop a better behavioral test. Courtship, a stereotyped, ritualized behavior ofDrosophila, involves complex motor and sensory functions in both sexes, which are controlled by large number of neurons; hence, behavior observed during courtship should be sensitive to disease processes in the nervous system. We used a series of traits c...

Parkinson's disease: animal models

Handbook of Clinical Neurology, 2007

) commercial reprints, selling or licensing of copies or access, or posting on open internet sites, personal or institution websites or repositories, are prohibited. For exception, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial Porras G, Fernagut P -O and Bezard E (2010) Parkinson's Disease: Animal Models. In: Kompoliti K, and Verhagen Metman L (eds.) Encyclopedia of Movement Disorders, vol. 3, pp. 420-424 Oxford: Academic Press.

Animal models of Parkinson's disease: a guide to selecting the optimal model for your research

Neuronal Signaling

Parkinson’s disease (PD) is a complex, multisystem disorder characterised by alpha synuclein pathology, degeneration of nigrostriatal dopaminergic neurons, multifactorial pathogenetic mechanisms and expression of a plethora of motor and non-motor symptoms. Animal models of PD have already been instructive in helping us unravel some of these aspects. However, much remains to be discovered, requiring continued interrogation by the research community. In contrast to the situation for many neurological disorders, PD benefits from of a wide range of available animal models (pharmacological, toxin, genetic and alpha-synuclein) but this makes selection of the optimal one for a given study difficult. This is especially so when a study demands a model that displays a specific combination of features. While many excellent reviews of animal models already exist, this review takes a different approach with the intention of more readily informing this decision-making process. We have considered ...

Promising rodent models in Parkinson's disease

Background: In the past decade, the study of the pathogenic mechanisms underlying neurodegeneration in Parkinson's disease (PD) has revealed a genetic component, often associated with a number of environmental risk factors. Animal models have improved our understanding of disease pathogenesis, providing significant insights into the understanding of novel molecular pathways. Each model has its own specific features and limitations, and the choice of the most appropriate one depends on the specific question that has to be answered. Aim: To provide an overview of some of the models supporting the hypothesis that early synaptic dysfunction represents a central event in the course of the disease. Development: Along with " classical " models, based on the administration of neurotoxins and capable of replicating the neuropathological hallmarks of the disease, a number of genetic models, reproducing the disease-causing mutations of monogenic forms of familial PD, have been generated. More recently, novel models have been developed, based on the combination of a toxic insult together with PD mutations, allowing for the identification of dysfunction at a prodromal disease stage. Conclusions: The development and characterization of new models is crucial for a better understanding of PD related-synaptopathy, and hold promise for the identification of novel therapeutics.