• Introduction

• Epidemiology

• Symptoms

• Pathology

• Aetiology

• Overview

• Pharmacological

• Other methods

Pathology

The two defining features of PD neuropathology are nigral neurodegeneration and Lewy body formation.

The neurodegeneration, or neuronal cell loss, is specific to a region of the brainstem known as the substantia nigra pars compacta. It involves neurons that produce the neurotransmitter dopamine (called dopaminergic neurons). More specifically, it involves a subset of these cells called "pigmented neurons". Pigmented cells are so-named because they contain neuromelanin. Neuromelanin is visible microscopically as a dark brown granular substance found within the cell body. It is the reason why the substantia nigra (literally, "black substance") appears dark to the naked eye.

The cell loss ultimately results in a significant decrease in brain dopamine levels (especially in a region of the brain called the striatum, to which these neurons project). Dopamine plays a highly important role in the neuronal circuits responsible for controlling and initiating movement. The brain can compensate for a certain degree of dopaminergic cell loss, but eventually these compensatory mechanisms prove inadequate. The characteristic PD symptoms start to appear when striatal dopamine levels have been reduced to about 20% of normal.

Lewy bodies are protein inclusions formed by abnormal aggregation of proteins within the cell body. They can occur throughout the brain, but their presence in the substantia nigra is diagnostic for PD. Brainstem Lewy bodies are generally spherical in shape and composed of a dense central "core" surrounded by a lighter peripheral "halo". However, cortical inclusions may differ greatly in shape to such so-called "classical" Lewy bodies.

The main constituent of Lewy bodies is a protein called alpha-synuclein. This protein, which has been localised to both the nucleus and the synapse (hence the name) is believed to be involved in the uptake of dopamine into small intracellular capsules called vesicles. It may also play a role in synaptic plasticity. Dysfunction of alpha-synuclein has been associated with a number of neurodegenerative disorders, called "synucleinopathies". Other proteins found within Lewy bodies include ubiquitin, parkin and neurofilaments. (Ubiqitin and parkin are involved in the ubiquitin-proteasome pathway, a biochemical pathway responsible for the degradation of abnormal or damaged proteins. Neurofilaments are neuronal structural proteins.) Mutations in the genes for these proteins have been linked with various familial forms of PD.