Dopamine and L-dopa Dissolve Protein Bundles Associated with Parkinson's and Alzheimer's Disease

Donato Di Monte, MD
The Parkinson's Institute, Sunnyvale, California
R01ES10806

Background: Many neurodegenerative diseases are characterized by the deposition of normally soluble proteins into insoluble amorphous deposits or fibers. Examples include Parkinson's, Alzheimer's disease, and Huntington's disease. In Parkinson's, a protein known as a-synuclein forms tangled bundles which are associated with the loss of dopamine-producing neurons in the substantia nigra region of the brain. In Alzheimer's disease, aggregation of the A peptide lead to the development of amyloid plaque formation followed by neurodegenerative changes. Although the relationship between protein deposits and neurodegeneration is unclear, neurologists think that the aggregation process is important in neuronal function impairment and it may ultimately lead to neuronal death.

Identifying compounds that inhibit protein deposition or reverse fibril formation could shed light on the role of protein deposits in human neurodegenerative diseases. Numerous compounds have been shown to inhibit specific amyloid fibril formation in vitro. Some have been reported to reverse A amyloid aggregation. Catecholamines and -synuclein have been found to inhibit fibrillation of a-synuclein. However, no compounds have been found to disassemble fibril bundles of a-synuclein. These investigators conducted experiments to determine the role of L-dopa (the precursor to dopamine), dopamine, and its metabolites on the fibrillation of a-synuclein.

Advance: The results showed that L-dopa and dopamine at physiologically relevant doses, dissolved fibrils of a-synuclein and A. The compounds also inhibited the formation of protein tangles. In further tissue culture experiments utilizing mouse brain slices containing a-synuclein deposits, incubation with L-dopa dissolved the protein deposits.

Implication: These findings could have important implications for understanding protein deposition diseases. If the protein deposits common in neurodegerative diseases contribute to neurologic impairment, disassembly of the fibrils by catecholamine compounds like L-dopa and dopamine may reverse or slow down disease progression. The ability to dissolve these protein bundles could provide a new approach for studying the consequences of protein aggregation and is also likely to assist in the development of interventions to prevent or treat neurodegenerative diseases.

Citation: Li J, Zhu M, Manning-Bog AB, Di Monte DA, Fink AL. Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson's and Alzheimer's disease. FASEB J. 2004 Jun;18(9):962-4. Epub 2004 Apr 01.