Parkinson's disease

Abstract

Parkinson's disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800's by James Parkinson as the 'Shaking Palsy'. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein.

Fig. 16.1

Typical Parkinsonism and Lewy Pathology. a Human midbrain image demonstrating loss of SNpc dopamine neurons in a PD subject. The midbrain was grossly dissected away from control (left; non-PD) and PD (right) brains. The white arrows indicate the right and left SNpc in a non-PD subject. Note the loss of pigmentation in the PD subject (black arrows) indicating a decreased number of melanin containing dopamine neurons. The image in Panel A was kindly contributed by Drs. Nabil Azzam and Rebekah Feng, Department of Neuroscience, Georgetown University College of Medicine. b H&E staining of a prototypical Lewy body in a SNpc dopamine neuron. Note the pink proteinaceous intracytoplasmic inclusion body (black arrow) within a SNpc dopamine neuron resulting in displacement of the normal brown pigmented melanin (white arrow). c Immunohistochemical staining for α-synuclein-positive Lewy bodies: seven micron thick, paraffin-embedded sections of cortex were labeled with an antibody directed against human α-synuclein. Note the intense brown labeling of the intracytoplasmic inclusion (black arrow). Images in Panels B & C are from a DLBD patient and were kindly contributed by Dr. William W. Pendlebury, University of Vermont College of Medicine. Brain tissue was kindly provided by the Georgetown University Medical Center and the University of Vermont College of Medicine Anatomical Gift Programs