The Science of Parkinson's

Pathological & Clinical Manifestations

Current therapies for PD are purely symptomatic and do not alter either disease progression or the underlying neuropathology that includes intraneuronal deposits of insoluble proteins known as Lewy bodies (Figure 2) and loss of pigmented neurons in the substantia nigra (Figure 3). These neurons normally project processes to the striatum where they produce and secrete the neurotransmitter dopamine.

              (Figure 2)

Progressive loss of these dopaminergic neurons in PD reduces the capacity of the remaining nerve endings in the striatum to synthesize dopamine in sufficient quantities (Figure 4). The resulting dopamine deficit alters the normal neural circuitry in a region of the brain called the basal ganglia, which is important for initiating voluntary movement, and gives rise to the clinically recognized motor symptoms of PD which include muscle rigidity, bradykinesia, resting tremor, and difficulty in maintaining upright posture.

             (Figure 3)

Other brain areas (cortical, subcortical, brainstem) where dopamine is not the primary neurotransmitter are also affected by Lewy body pathology indicating that PD pathology, is more widespread and not specific to dopamine-producing neurons. This multisystem degeneration likely underlies the psychiatric disturbances prevalent in PD patients. For example, depression and dementia affect ~50% of PD patients, and the rate of cognitive decline in PD dementia is comparable to that in Alzheimer's disease.

            (Figure 4)

The majority of PD cases are considered sporadic, where there is little or no verifiable family history of the disorder, underlying the complex and heterogeneous etiology of the disorder. However, in a small number of cases, familial PD has been identified as an inheritable trait. Genetic analyses of these PD families have revealed several genes with strong linkage to PD as a result of mutations. Scientists at the Tanz CRND and in many laboratories around the world are working to understand how the proteins encoded by these genes might fit into one or more biochemical cascades that can be manipulated in PD patients by pharmacological or genetic therapies in order to prevent or halt the degeneration at an early stage.













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