As it was explained to me, the dopamine pathways back up leaving no where for it to go so it begins to destroy itself. Levodopa can get through the blood brain barrier and substitute, though it be not as efficient as dopamine.
Which is why it is so hard to stay on an even keel. Too much levodopa and you add to the damage; not enough and you can't function. What role the other drugs play, I am not sure of.

This information was first reported in the pathological study of patients who had a Parkin malformation.

1. Reviews in Neurological Diseases, Vol 1, No 3., 2004, author John J. Kelly, M.D., The George WashingtonUniversity Medical Center, Washington D.C.
"Researchers from Switzerland, studied a more common, recessive form of inherated Parkinson's disease that typically strikes before the age of 40 and is linked to a mutation in the Parkin gene. The loss of enzyme activity resulting results in an accumlation of protein substrates, including alpha synuclein, in the cell. In these juvinile Parkinson's cases, lewey bodies do not generally present.

In these forms of the disease involving buildup of alpha synuclein in the cell, would result in degeneration and death (of the cell.)

Paula, this is what the GDNF factor was about. By combining a virus and Parkin and delivering it into the cells, protected the cells from neurotoxicity.

2. "Protecting microtubule "highways" may lead to novel therapies", Medical Neurology, 12.6.2004 states that Parkinson's disease may be caused by a double whammy; mutated Parkin genes combined with the highly toxic chemical rotenene, results in a cascade of highly toxic free radicals, the destruction of microtubules that transport dopamine to the brain's movement center, and eventioal death of the dopamine producing neuron.

3. "Progression of nigrostriatal dysfunction in a parkin kindred: an [FDOPA PET and clinical study. MRC Clinical Sciences Centre, London, England. Received November 21, 2001, Revised March 27, 2002, Accepted April 24, 2002.
"Neuropathology of Parkin cases is limited but, in cases that have been reported, there was a generalized loss of dopaminergic neurones in the substantia nigia pairs compacta without Lewy body inclusions. ...subclinical nigrostriatal dysfunction has been demonstrated in carriers of a single mutent parkin allele (Hilker et al, 3001). RESILTS <eam age pf pmset su,[tp,s was 29 uears (ramge 28 - 32 years). All affected siblings ha a striking response to L-dopa therapy, with levodopa-related dyskinesias after a mean interval of 2.4 years. Estimated mean clinical disease was 26 years (range 19 - 32 years) at the time of the second scan. The clinical presentation of the patients was comparable with that of juvenile-onset parkinsonism; however, currently their phenotype was indistingshable from IPD, with a common feature of severe resting leg tremor.

4. "Parkin Stabilizes Microtubiles Through Strong, Binding Mediated by t=Three Independent Domains."" The American Society for Biochemistry and Molecular Biology. From Department of Physiology and Biophysics and Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY

5. Parkin counteracts symptoms in a Drosohila model of Parkinson's disease.
Annika FM Heywood and Brian E. Staveley, Univerisity of Newfoundland, Department of Biology, St. John's, Newfoundland and Labrador, Canada. Publlish 16 April, 2004. BMC Neuroscience.
Conclusions: Our experiments demenstrate that the directed expression of the parkin gene counteracts the PD-like symptoms."

6. Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism, Brain Vol 127 No 6, 2004.

Tired of typing. Going back to bed. I have followed this trail of infor for many years.

Sincerely,
Vicky