Injection of the endogenous methyl donor, S-adenosyl
methionine (SAM), into rat brain induces
Parkinson's disease (PD)-like symptoms possibly by stimulating deleterious
protein methylation. Gel-filtration chromatography of rat brain extracts treated with [3H-methyl]-SAM revealed the presence of radioactive peaks with apparent molecular weights of about 5 kDa. Treatment with
guanidine HCl altered the elution volumes of the labeled peaks. Lyophilized peak fractions released volatile 3H-methanol on incubation with NaOH, indicating the presence of carboxyl methyl
esters. Because prenylated
proteins are avid methyl acceptors at the terminal
carboxylic acid groups, 1 micromol
S-farnesylcysteine (FC) analogs blocked the SAM-induced
tremors in the experimental rats. FC analogs did not only reverse the associated rigidity, abnormal posture, and
hypokinesia, but stimulated hyperactivity in the animals. This
amphetamine-like effect was monitored for 20 min in an animal activity monitor and movement times between 400 +/- 100 and 560 +/- 125 s covering distances between 78 +/- 29 to 125 +/- 35 m were recorded for rats treated with FC analogs with or without SAM. Control animals moved only for 60 +/- 13 s covering about 6 +/- 1 m, indicating a 7-9-fold and 13-21-fold increase in duration of movement and distance covered, respectively.
N-Acetyl-S-farnesylcysteine (AFC) potentiated
amphetamine-induced ipsiversive rotation of 6-hydroxydopamine-lesioned rats from 390 +/- 130 to 830 +/- 110, with AFC alone having no significant effect on net rotation compared to controls. These data indicate that intracerebroventricular injection of SAM may induce PD symptoms by interfering with the methylation/demethylation homeostasis of prenylated
proteins that function in the dopaminergic and other signaling pathways, and that the FC analogs may counteract the SAM effects by acting synergistically on events subsequent to
neurotransmitter release.