The first major scientific observation regarding PD was the finding that
 cells were lost from a cluster deep in the brain termed the substantia
 nigra. The name of this structure reflects the brown-black pigment that
 makes them stand out. It was later found that in patients with PD the cells
 in the substantia nigra contain a round blue staining structure called a
 Lewy body. Because the cells of the substantia nigra get progressively
 sick and die, PD is currently classified as a "degenerative" disease. Other
 degenerative diseases are Alzheimer's disease, amyotrophic lateral
 sclerosis (ALS, Lou Gehrig's disease), progressive supranuclear palsy,
 multiple system atrophy, Huntington's disease, among others. They all
 share the feature of progressive cell loss in one region or in one system of
 the nervous system without a known cause. The degenerative category is
 a temporary one until the fundamental cause is found for the selective cell
 damage in each disease. Abnormal structures similar to the Lewy bodies,
 called inclusions, are contained in nerve cells in many of the degenerative
 diseases.

 It was later discovered that the cells in the substantia nigra make the
 chemical substance dopamine. Almost all the symptoms of PD can be
 traced to the lack of dopamine in the substantia nigra. Dopamine is used
 by the substantia nigra to signal between groups of nerve cells in a
 collection of structures known as the basal ganglia that is located deep in
 the cerebral hemispheres. The basal ganglia are responsible for
 modulating, or modifying all movements. They do not themselves produce
 or initiate movement (the cells of the cerebral cortex on the outside of the
 brain do this) but they influence the readiness, starting, stopping, speed,
 and smoothness of movement. Excessive activity of the basal ganglia
 causes unwanted and unnatural movements-as occurs in Huntington
 chorea or when too much L-dopa is ingested, while diminished activity in
 the basal ganglia causes a reduction in the amount and speed of
 movement, typical of PD. How a disruption of the circuits within the basal
 ganglia gives rise to tremor is not precisely known.

 Replacing the dopamine that is lacking in order to reverse the effects of
 PD proved difficult because it is not absorbed when taken orally and does
 not get into the brain. As a result, the drug L-dopa (chemical name for
 L-dihydroxyphenylalanine) was developed. It is taken up by the brain and
 changed by the remaining cells of the subtantia nigra into dopamine. A
 number of chemicals are able to prolong the effects of L-dopa and to
 reduce its side effects. Medications that act directly on the target cells of
 the subtantia nigra in a way that imitates dopamine (dopamine agonists
 such as bromocriptine and ropinirole) are alternative treatments that have
 been developed in recent years.

 The underlying cause of cell degeneration and the nature of the Lewy
 bodies is an area of very active study. Information so far suggests that an
 excess of certain proteins, one in particular called synuclein, clogs up the
 cells of the subtantia nigra. Synuclein is one of the main components of
 Lewy bodies. A hint regarding the cause of PD comes from several
 families in which the disease is inherited and comes on at an early age.
 The error in the genes in these families relates to an excess of synuclein.
 Most patients with PD do not, however, have a genetic error of this nature
 but by studying the way in which the genes in these families cause the
 Lewy bodies and cell damage, it is hoped that insights will be gained into
 typical PD. Another line of investigation has come from the observation
 that the toxic chemical "MTPT" causes damage very specifically to cells
 of the substantia nigra and results in an illness very much like PD. This
 suggests that a toxin either in the environment, or one produced within the
 brain, might cause damage to the substantia nigra in PD. It is also
 possible that the "toxin" is harmful only in individuals who lack the ability
 to rid the brain of the chemical or who have a genetic makeup that
 produces more of certain chemicals that are normally harmless in smaller
 amounts. One candidate for such a toxin is "free radicals" which are the
 byproducts of many chemical reactions in brain cells. All of these areas of
 research, and several others, are being actively pursued.