Parkinson's Disease

Molecular and Therapeutic Insights From Model Systems

Richard Nass, Serge Przedborski

• Publisher: Academic Press
• Year: 2011
• ISBN:
  9780080559582
• Topic: Medicine
• Subtopic: Pharmacology

Parkinson's disease is the second most prevalent neurodegenerative disease and is characterized by the irreversible loss of dopamine neurons. Despite its high prevalence in society and many decades of research, the origin of the pathogenesis and the molecular determinants involved in the disorder has remained elusive. Confounding this issue is the lack of experimental models that completely recapitulate the disease state. The identification of a number of genes thought to play a role in the cell death, and development of both toxin and genetic models to explore the function of the genes both in unaffected and diseased cells are now providing new insights into the molecular basis of the neurodegeneration, as well as therapeutic approaches. In this reference, we will describe the advances and the advantages that various invertebrates, cell culture, rodents, and mammals provide in the identification of the molecular components and mechanisms involved in the cell death, and outline the opportunities that these systems provide in drug discovery.

• Comprehensive and critical assessment of the utility of various model systems to identify the molecular components and pathways involved in Parkinson's disease
• Describes the power of toxin and genetic models to identify novel therapeutic targets and compounds that can be used in PD
• Current overviews of current status of PD research and discovery from bench-to-bedside
• Provides novel insights and views on where the future of PD research may lead
• Provides a powerful teaching tool and template to explore the utility of model systems to identify molecular pathways, molecular targets, and therapeutics that are applicable to a variety of neurological diseases

Part I. Clinical Overview

Chapter 1. Clinical Aspects of Parkinson Disease

Clinical Features of Parkinson Disease

Parkinsonism is defined as any combination of six specific, independent motoric features: tremor-at-rest, bradykinesia, rigidity, loss of postural reflexes, flexed posture, and the freezing phenomenon (where the feet are transiently “glued” to the ground) (Table 1.1). Not all six of these cardinal features need be present, but at least two should be before the diagnosis of parkinsonism is made, with at least one of them being tremor-at-rest or bradykinesia. Parkinson disease (PD) is the type of parkinsonism that is most commonly encountered by the general clinician; it is also the one on which much research has been expended and the one we know the most about. The great majority of cases of PD are sporadic, without any other family members being affected. One of the great advances in the last decade is that several gene mutations have been discovered to cause PD. But these monogenetic causes do not explain the great majority of sporadic cases. Environmental factors of an unknown nature and the combination of genetic and environmental risk factors are considered to play a role in the etiology of PD.

TABLE 1.1. Cardinal motor features of parkinsonism

Tremor-at-rest

Bradykinesia/hypokinesia/akinesia

Rigidity

Flexed posture of neck, trunk, and limbs

Loss of postural reflexes

Freezing of gait

The symptoms of PD begin insidiously and worsen gradually over time. They typically begin on one side of the body, rather than bilaterally, before eventually spreading to involve the other side. The most common initial symptom recognized by the patient is tremor of a hand or foot when that limb is at rest, called tremor-at-rest or resting tremor with a frequency of about 4 Hz.The hand is the more common site. The tremor can be intermittent at the beginning, being present only in stressful situations. Later, tremor tends to be more constant. Tremor is not present in everyone with PD. When absent, the initial symptom is a reduced arm swing or a decreased stride length and speed when walking.

Although PD can develop at any age, it is most common in older adults, with a peak age at onset around 60 years. The prevalence and incidence increases with age, with a lifetime risk of about 2%. A positive family history doubles the risk of developing PD to 4%. Twin studies indicate that PD with an onset under the age of 50 years is more likely to have a genetic relationship than for patients with an older age at onset.

Of the six cardinal motor symptoms, three occur early in the course of the illness, and three occur later. The early symptoms and signs are rest tremor, bradykinesia, and rigidity. Bradykinesia is slowness and reduced amplitude of movement. Features of limb bradykinesia are a smaller and slower of handwriting, difficulty shaving, brushing teeth, and putting on make-up. Walking becomes slow, with decreased arm swing and with a tendency to shuffle feet. Difficulty arising from a deep chair, getting out of automobiles, and turning in bed are symptoms of truncal bradykinesia. Rigidity of muscles is detected by the examiner when he/she moves the patient's limbs, neck or shoulders and experiences increased resistance. There is often a ratchet-like feel to the muscles, so-called cogwheel rigidity.

PD is a neurodegenerative disease, and these early motoric symptoms appear to be related to striatal dopamine deficiency due to loss of dopaminergic neurons in the substantia nigra pars compacts, which sends axons to the striatum. Whereas these early features of PD usually respond to medication that activate striatal dopamine receptors (such as levodopa and dopamine agonists), the three later motoric symptoms of flexed posture, loss of postural reflexes a...

Table of contents

• Brief Table of Contents
• Table of Contents
• List of Figures
• List of Tables
• List of Contributors
• Preface
• Foreword
• Part I. Clinical Overview
• Part II. Non-Human Primate Models
• Part III. Rodent Toxin Models
• Part IV. Rodent And Other Vertebrate Genetic Models
• Part V. Multicellular Invertebrate Models
• Part VI. Cell-Based Models
• Part VII. Cell-Free Models