Depletion of AADC activity in caudate nucleus and putamen of Parkinson's disease patients; implications for ongoing AAV2-AADC gene therapy trial.
In Parkinson's disease (PD), aromatic L-amino acid decarboxylase (AADC) is the rate-limiting enzyme in the conversion of L-DOPA (Sinemet) to dopamine (DA). Previous studies in PD animal models demonstrated that lesion of dopaminergic neurons is associated with profound loss of AADC activity in the striatum, blocking efficient conversion of L-DOPA to DA. Relatively few studies have directly analyzed AADC in PD brains. Thus, the aim of this study was to gain a better understanding of regional changes in AADC activity, DA, serotonin and their monoamine metabolites in the striatum of PD patients and experimentally lesioned animals (rat and MPTP-treated nonhuman primate, NHP). Striatal AADC activity was determined post mortem in neuropathologically confirmed PD subjects, animal models and controls. A regional analysis was performed for striatal AADC activity and monoamine levels in NHP tissue. Interestingly, analysis of putaminal AADC activity revealed that control human striatum contained much less AADC activity than rat and NHP striata. Moreover, a dramatic loss of AADC activity in PD striatum compared to controls was detected. In MPTP-treated NHP, caudate nucleus was almost as greatly affected as putamen, although mean DA turnover was higher in caudate nucleus. Similarly, DA and DA metabolites were dramatically reduced in different regions of PD brains, including caudate nucleus, whereas serotonin was relatively spared. After L-DOPA administration in MPTP-treated NHP, very poor conversion to DA was detected, suggesting that AADC in NHP nigrostriatal fibers is mainly responsible for L-DOPA to DA conversion. These data support further the rationale behind viral gene therapy with AAV2-hAADC to restore AADC levels in putamen and suggest further the advisability of expanding vector delivery to include coverage of anterior putamen and the caudate nucleus.
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States of America.
Agnieszka
A
Ciesielska
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States of America.
Lluis
L
Samaranch
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States of America.
Waldy
W
San Sebastian
Mayo Clinic, Jacksonville, FL, United States of America.
Dennis W
DW
Dickson
Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America.
Samuel
S
Goldman
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States of America.
John
J
Forsayeth
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States of America.
Krystof S
KS
Bankiewicz
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000627:therapeutic use; D008253:Macaca mulatta; D008297:Male; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D011699:Putamen / Q000378:metabolism*; D051381:Rats
D007980:Levodopa; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine