PROJECT SUMMARY (See instructions):
Parkinson’s disease (PD) affects more than a million persons in the U.S. and is the 2nd most common
progressive, neurodegenerative disease. Early on, the movement deficits (tremor, rigidity, slowed movement,
altered gait), usually respond to oral levodopa (L-DOPA) and other medications. However, with disease
progression, L-DOPA’s effectiveness gradually diminishes and dyskinesia and motor fluctuations emerge.
Most symptoms of PD are due to a reduction of dopamine (DA)-secreting cells in the substantia nigra. In PD,
L-DOPA restores function by replacing lost DA. Endogenous L-DOPA and DA concentrations are largely
regulated by astrocytes, which maintain extracellular homeostasis. Although astrocytes have several
transporter systems for monoamine uptake, including DA, we have shown that astrocytes take up excess of
DA via low-affinity, high-capacity Uptake2 transporters. We also demonstrated that astrocytes wrapping around
blood vessels take up L-DOPA and contain monoamine oxidase (MAO) type B which oxidizes DA taken up by
We hypothesize that astrocytes take up and oxidize the vast majority of DA converted from L-DOPA, especially
when DA neurons are severely degenerated due to PD. Reducing the ability of astrocytes to take up DA
through use of specific transporter blockers may permit the use of lower doses of L-DOPA, thereby diminishing
DA pulsatility and motor fluctuations. This hypothesis will be tested here in 3 Aims.
Aim 1. Identify the specific transporter molecules involved in dopamine reuptake by astrocytes using brain slice
and cell culture models.
Aim 2. Identify which specific transporter blockers can slow DA reuptake using an astrocyte brain slice model.
Aim 3. Identify which Uptake2 blockers are effective in reducing therapeutic L-DOPA concentrations in a whole
animal model of PD.
The results will greatly enhance the understanding of the role of astrocytes in PD etiology and pave the way to
the development of preventive measures for L-DOPA-induced dyskinesia.