Decreased L-Aromatic-Amino-Acid Decarboxylase Activity and Vesicular Storage Contribute to Putamen Dopamine Depletion in Parkinson’s Disease and Multiple System Atrophy (P6.385)

Objective: We used putamen tissue levels of cysteinyl and parent catechols to assess dopamine synthesis and vesicular storage in Parkinson’s disease (PD) and multiple system atrophy (MSA).Background: Drastic loss of dopamine in the striatum causes the parkinsonism found in PD and MSA. The severity of putamen dopamine depletion exceeds that explained by denervation alone. Decreased L-aromatic-amino-acid decarboxylase (LAAAD) activity and vesicular storage in residual terminals could make up the difference, and gene therapy trials are attempting to increase LAAAD activity and vesicular uptake; however, post-mortem neurochemical confirmation of these abnormalities is incomplete. Cysteinyl-DOPA and cysteinyl-dopamine are formed from spontaneous oxidation of the parent compounds in the neuronal cytoplasm. Cysteinyl-DOPA is not a substrate for LAAAD, so decreased LAAAD would be expected to decrease cysteinyl-dopamine with respect to DOPA. Cysteinyl-dopamine is not co-stored with dopamine, so a vesicular storage defect would be expected to increase cysteinyl-dopamine with respect to dopamine. If decreased LAAAD activity and vesicular storage occurred together in series, then Cys-DOPA would be substantially increased with respect to dopamine. We used post-mortem measurements of cysteinyl and parent catechols in putamen tissue to evaluate these possibilities in PD and MSA.Design/Methods: Putamen tissue samples from 17 PD and 21 MSA patients and from 25 controls were assayed for cysteinyl and parent catechols simultaneously.Results: In PD and MSA, cysteinyl-dopamine:DOPA ratios were decreased to 13[percnt] and 23[percnt] of control (pu003c0.0001 each) and cysteinyl-dopamine:dopamine ratios increased to 195[percnt] and 307[percnt] of control (p=0.04, p=0.03). Cysteinyl-DOPA:dopamine ratios were markedly increased (47 and 79 times control, pu003c0.0001 each).Conclusions: PD and MSA entail post-mortem neurochemical evidence for both low LAAAD activity and decreased vesicular storage, which contribute to putamen dopamine depletion and thereby clinical status. The results support efforts to increase LAAAD activity and vesicular uptake by gene therapy approaches in these diseases. Disclosure: Dr. Goldstein has nothing to disclose. Dr. Jinsmaa has nothing to disclose. Dr. Holmes has nothing to disclose. Dr. Mash has nothing to disclose. Dr. Kopin has received personal compensation for activities with Nippon Zoki Pharmaceuticals and Rikaken USA, Inc. as a consultant. Dr. Sharabi has nothing to disclose.