History of Parkinson's Disease Research
Parkinson's disease (PD) is a chronic progressive disorder first described in the early 1800s by James Parkinson and is characterized by slowness, stiffness, and tremor. These symptoms are due to the loss of midbrain dopaminergic neurons, which causes the depletion of dopamine within the basal ganglia and the disruption of motor and cognitive circuitry. The disease, however, affects many other neuronal systems, resulting in a wide range of motor (balance impairments) and non-motor symptoms that can precede the motor deficits by many years. Although the cause of PD remains unknown, environmental and genetic interactions are thought to underlie disease etiology. A number of animal models have provided insight about pathophysiology and treatment. These models include pharmacological, neurotoxin, and genetic-based approaches, with the overall goal of replicating aspects of the human condition, including, but not limited to, dopamine depletion and cell death. Historically, pharmacological approaches were valuable in first elucidating dopamine as an important neurotransmitter for motor and basal ganglia function. Using rabbits exposed to reserpine, Arvid Carlsson, who shared the Nobel Prize in 2000, linked motor behavioral impairments with depletion of the neurotransmitter dopamine. This discovery led to the strategy of replacing the missing neurotransmitter through the oral administration of levodopa (L-DOPA), a dopamine precursor, combined with carbidopa, a peripheral inhibitor of dopamine metabolism.
Two well-established neurotoxin models, using 6-hydroxydopamine (6-OHDA) and 4-methyl, 1,2,3,6 tetrahydropyridine (MPTP), have enabled scientists to replicate PD in rodents and non-human primates. This can enable the identification of compounds effective for anti-Parkinsonian symptomatic treatment, as well as exploring novel therapeutic approaches such as transplantation and gene therapy. Genetic animal models are particularly useful for examining mechanisms of pathology, including the role of protein misfolding, the mitochondria, and autophagy. In addition, these models are used to develop and test neuroprotective therapies to stop the course of disease.
Studies using non-human primates helped locate the aberrant circuit activity resulting from dopaminergic neuron death in a region of the brain called the basal ganglia during PD. Small regions in this circuit now serve as a target for surgical approaches such as deep brain stimulation, which compensates for the loss of dopaminergic signaling, thereby alleviating PD symptoms as well as motor complications.
