• Introduction

• Epidemiology

• Symptoms

• Pathology

• Aetiology

• Overview

• Pharmacological

• Other methods

Alpha-synuclein

A protein found throughout the brain, in the nuclei and at the synapses of neurons. It is one of the main components of Lewy bodies, and mutations in its gene have been linked with familial forms of the disease. For this reason, PD is referred to as a synucleinopathy.

The precise function of alpha-synuclein is unknown, but it is believed to be involved in vesicle formation, and may play a part in synaptic plasticity. There are two other members of the synuclein family, and these are called beta- and gamma-synuclein.

Alzheimer's disease

The most common neurodegerative disease, AD is characteristed clinically by dementia and memory loss. Like PD, the pathological symptoms include neuronal loss and abnormal protein deposition, but different regions and proteins are involved.

Dementia

The dementia seen in about 30% of PD cases is characterised by memory loss and a sharp decrease in cognitive function. It generally develops subsequent to motor symptoms, unlike dementia with Lewy bodies (DLB), in which the mental symptoms appear first. The clinical presentation of PD and DLB patients grows more and more similar as the diseases progress. This, together with the neuropathological evidence, raises the possibility that both are variants of the same underlying disorder.

Eosin

Eosin is a histological stain routinely used in neuropathology. It stains various cytoplasmic cellular components — including the proteins found in Lewy bodies — red to pink, allowing them to be distinguished by light microscopy. Such components are described as eosinophilic, for their ability to bind the dye.

Eosin is commonly used in conjunction with haematoxylin, or haemalum, (see below). The combined stain is generally referred to as H&E.

Haematoxylin

A routine histological dye which stains nuclei blue, making it possible to determine the orientation and anatomy of a tissue section. For this reason, haematoxylin (also called haemalum) is often used in as a counterstain (in conjunction with immunohistochemistry, for example).

Idiopathic

Of unknown cause. Most cases of PD are idiopathic, with no clearly defined genetic or environmental agent able to be identified as a causative factor.

Immunohistochemistry

• Introduction

• Epidemiology

• Symptoms

• Pathology

• Aetiology

• Overview

• Pharmacological

• Other methods

Lewy bodies

Lewy bodies are protein inclusions found in the cytoplasm of surviving dopaminergic neurons in PD and a number of other disorders. They can occur throughout the brain, not just in the neurons of the substantia nigra (where their presence is diagnostic for PD). So-called "classical" Lewy bodies — first described in the Nucleus Basalis of Meynert — are spherical in shape and consist of a dense central "core" surrounded by a fibrillar "halo". This description is typical of brainstem inclusions, but those seen in the cortex often exhibit different morphologies.

The three main components of Lewy bodies are the proteins alpha-synuclein, parkin and ubiquitin. It is believed that accumulation of alpha-synuclein within intracellular transport fibrils is the primary event in Lewy body formation. Abnormal protein molecules aggregate as they migrate from the endoplasmic reticulum (the site of post-translational modification) to the periphery of the cell. Parkin and ubiquitin — so-called "scavenger proteins" — are believed to become incorporated into the forming inclusion as they attempt to break it up (secondary formation events). Exceptions to this sequence of events are seen in a rare form of juvenile PD found in Japan, where parkin aggregation is the initiating event, and a rare familial form of the disease involving ubiquitin aggregation in the primary formation stage.

Figure One: A section of neural tissue, stained with haematoxylin (blue) and eosin (pink), showing three Lewy Bodies.

Mental symptoms

The mental symptoms observed in some PD patients can include dementia, hallucinations and behavioural changes. When they occur, they tend to do so later in the disease process, after the development of physical symptoms.

Movement disorder

Abnormalities of movement can include reduced mobility (such as the rigidity and bradykinesia seen in PD) and excessive or inappropriate motion (e.g., the dyskinesias that may occur as side-effects of some PD treatments). Such abnormalities may result from muscular or neurological problems. (The latter may involve central or peripheral nerves.) In the case of PD, the physical symptoms are caused by the loss of those neurons responsible for initiating and controlling movement from the substantia nigra.

Neurodegenerative disease/disorder

A neurodegenerative disorder is one involving neuronal cell death. Many are progressive, meaning that the degeneration is an ongoing process. Often, symptoms do not appear until a threshold is reached. With PD, this threshold is 80% dopamine depletion. Up to this point, it is believed that compensatory mechanisms can maintain adequate functionality of the afflicted brain region(s).

Parkin

A ubiquitin ligase enzyme. Mutations in the gene for Parkin have been linked with an autosomal recessive juvenile form of familial PD.

Substantia nigra

A part of the midbrain involved in the control of movement. The loss of dopaminergic neurons from this region is characteristic of PD pathology.

Synucleinopathy

The synucleinopathies are a group of neurodegenerative disorders exhibiting synuclein pathology. This is typified by the presence of intracytoplasmic protein inclusions composed largely of alpha-synuclein fibrils. (Examples of these inclusions are the Lewy bodies and Lewy neurites seen in PD.) However, hippocampal accumulation of beta- and gamma-synuclein has been seen in some cases of PD and dementia with Lewy bodies (DLB).

Ubiquitin

A small molecular-weight heat-shock protein present throughout the whole brain, and one of the main components of Lewy bodies after alpha-synuclein. Proteins to be degraded by the proteasome are first "tagged" by ubiquitin molecules. It is thought that its presence in Lewy bodies may reflect some failure of the "ubiquitin-proteasome system" (UPS).

Ubiquitin ligase

An enzyme that adds a ubiquitin molecule onto a protein so that it can be recognised and degraded by the proteasome.

Ubiquitin-proteasome system

The intracellular system responsible for degrading abnormal, damaged or mis-folded proteins. In order to be recognised by the UPS, a protein must first be tagged with ubiquitin molecules through the action of one of a class of enzymes called "ubiquitin ligases".

Young-onset PD