Chapter 11 - Genetic Mouse Models of Neurodegenerative Diseases

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Neurodegenerative diseases are generally characterized by the selective degeneration of particular neuronal populations and the accumulation of abnormal or aggregated proteins within, but occasionally external to, neurons in affected brain regions. These diseases can be broadly classified as disorders of cognition and memory or movement, and both features can often coexist in a single disease. In recent years, the identification of genetic mutations that cause rare monogenic familial disease has revolutionized our understanding of the molecular basis of neurodegenerative disease and has provided new targets for the development of disease-modifying therapies. An essential part of this process has been the development of genetic animal models that accurately recapitulate the essential features of each disease, with particular emphasis on the use of mouse models. Such mouse models have provided unique insight into the molecular mechanism(s) through which genetic mutations precipitate neurodegeneration and produce associated clinical and pathological phenotypes. In this review, we provide an overview of the current status, uses and limitations of genetic mouse models for understanding major neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis.

Introduction

Neurodegenerative diseases are a collection of related disorders that are each characterized by the selective degeneration of one or more specific neuronal populations together with the accumulation of abnormal or aggregated proteins in affected neurons or brain regions. Such selective neurodegeneration and associated neuropathology give rise to distinct yet often overlapping clinical symptoms which most often affect cognition, memory, and movement. Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder that is characterized by a profound dementia. The underlying neuropathology consists of cortical and subcortical neuronal degeneration with the appearance of extracellular plaques consisting of amyloid β (Aβ) peptide and intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) comprise other major causes of dementia characterized by selective neuronal loss together with tau, ubiquitin, or TDP-43-positive inclusions in FTD or α-synuclein-positive Lewy bodies in DLB. Parkinson's disease (PD) is the most common neurodegenerative movement disorder whereas Huntington's disease (HD) is comparatively less common. PD is characterized by the relatively selective loss of dopaminergic neurons of the substantia nigra pars compacta leading to a loss of dopaminergic input into the striatum. PD similar to DLB is characterized by the appearance of Lewy bodies in surviving neurons of the brainstem. PD pathology often extends to areas of the cerebral cortex and resulting dementia is a common symptom. HD is primarily due to the selective degeneration of medium-sized spiny output neurons in the caudate putamen and caudate nucleus leading to the abnormal control of movement, but subjects can also develop cognitive decline and dementia owing to cortical dysfunction and degeneration. HD is neuropathologically characterized by the appearance of neuronal nuclear inclusions composed of aggregated polyglutamine (polyQ)-expanded huntingtin (Htt) protein. Other less common neurodegenerative movement disorders include various forms of dystonia, progressive supranuclear palsy, corticobasal degeneration, and spinocerebellar ataxias. A final group of neurodegenerative disorders affect spinal cord motor neurons or the peripheral nervous system, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophies, and peripheral neuropathies that impair motor and autonomic function. In the case of ALS, motor neurons of the spinal cord progressively degenerate with the appearance of cytoplasmic inclusions that contain ubiquitin and/or TDP-43 proteins. In each neurodegenerative disease, the inclusion-forming protein provides clues to the underlying mechanism of the sporadic form of disease and genetic mutations in the corresponding gene often cause a rare, earlier-onset, monogenic familial form of the disease. For example, mutations in the amyloid precursor protein (APP) which normally gives rise to Aβ peptide as well as Aβ plaques in sporadic AD cause autosomal-dominant familial AD, whereas mutations in α-synuclein, the major component of Lewy bodies in sporadic PD, cause autosomal-dominant familial PD. This suggests that the inclusion-forming protein may underlie the molecular basis of sporadic disease.

The identification of genetic mutations that cause rare familial monogenic forms of neurodegenerative disease has revolutionized our understanding of the underlying molecular basis of disease and has provided a number of potential targets for the development of disease-modifying therapies. Here, the development and utilization of genetic animal models that faithfully mimic disease, or at least important aspects of disease, have proved of immense value and have provided the basis for preclinical validation of new therapeutic compounds. A number of genes have been identified that when mutated cause familial forms of AD, PD, and ALS. In the case of HD, which is generally considered to be an inherited disease with some exceptions, polyQ expansions in the Htt protein above a critical threshold underlie the vast majority of cases. In most of these diseases, the mutated gene products tend to fall within common molecular pathway(s) or are in some way related to the underlying neuropathology, with the exception being PD where a common disease pathway has so far remained elusive. The development of genetic animal models serves three major roles: (i) the elucidation of the normal physiological function of the gene product (i.e., in knockout (KO) mice or transgenic mice overexpressing the wild-type (WT) protein); (ii) understanding how genetic mutations precipitate neuronal degeneration (i.e., knockout and knockin mice, or transgenic mice overexpressing the mutated protein); and (iii) the development of models with disease-relevant phenotypes that are critical models for preclinical testing of therapeutics. Mice have been widely used to model the effects of familial mutations because the introduction of genetic mutations is relatively straightforward and they are behaviorally and neuroanatomically well characterized. However, the use of rats is becoming ever more popular due to the advent of new methods for their genetic manipulation. Thus, genetic mouse models play an important role in providing formal proof that a particular genetic mutation is disease-causing in vivo, and in understanding how protein dysfunction owing to gain- or loss-of-function mutations induces neuronal degeneration. In this review, we provide a current overview of the various genetic mouse models that have been developed to model familial mutations associated with major neurodegenerative diseases.

Section snippets

Mouse Models for Autosomal-Dominant Parkinson's Disease (α-Synuclein and LRRK2)

Mutations in the α-synuclein and leucine-rich repeat kinase 2 (LRRK2) genes unambiguously cause autosomal-dominant, familial forms of PD.1α-Synuclein (PARK1 and 4; OMIM 163890) was the first gene identified to cause familial PD.2 Point mutations (A53T, A30P, and E46K) or gene multiplications (i.e., duplications and triplications) cause rare forms of familial PD.2, 3, 4, 5 In general, mutations in the α-synuclein gene are an exceedingly rare cause of familial PD. Recent genome-wide association

Mouse Models of Alzheimer's Disease

AD is the most common form of dementia and neurodegenerative disease. AD has a chronic and progressive course with manifestation of clinical symptoms usually above the age of 65 years although there are less common early-onset forms of AD (refer to www.alzforum.org). AD is characterized neuropathologically by extracellular senile plaques consisting of aggregated Aβ peptide (of 39–43 amino acids), intraneuronal NFTs consisting of filamentous hyperphosphorylated tau protein, and severe cortical

Mouse Models for HD

HD (OMIM 143100) is a progressive neurodegenerative disorder with age at onset between 30 and 40 years with juvenile-onset in some cases. The vast majority of HD cases are familial with autosomal-dominant inheritance, while sporadic cases are rare. There is a prodromal phase of disease lasting for up to 10 years with mild psychotic and behavioral symptoms that precede the characteristic motor symptoms. The clinical symptoms of HD are characterized by a progressive chorea, dystonia, impaired

Mouse Models for ALS

ALS is a rare adult-onset motor neuron disease, which affects both upper and lower neurons of the spinal cord and is clinically characterized by progressive weakness, spasticity, paralysis, and death within 3–5 years of initial symptom onset.351 Most ALS cases are sporadic (SALS) with unknown etiology, whereas 10% are familial (FALS).351, 352 The majority of familial cases are caused by missense mutations in the Cu-Zn-superoxide dismutase (SOD1, ALS1) gene (OMIM 147450) and occur in an

Conclusions

Genetic mouse models of neurodegenerative disease provide important tools for understanding the molecular basis of familial disease with the expectation that similar mechanisms are conserved and account for sporadic disease. Mouse models have provided critical proof that disease-associated mutations identified in human disease are responsible for, and can often recapitulate, neurodegeneration and associated behavioral deficits and pathologies. Such models should also ideally reproduce key

Acknowledgments

We apologize to our colleagues whose important research we were unable to cite due to space limitations. The authors are grateful for funding support from the Ecole Polytechnique Fédérale de Lausanne, Swiss National Science Foundation (grant no. 310030_127478), Michael J. Fox Foundation for Parkinson's Research, and Parkinson Schweiz.

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