Increased vulnerability to L-DOPA toxicity in dopaminergic neurons From VMAT2 heterozygote knockout mice.
Parkinson's disease (PD) is characterized by a preferential loss of dopaminergic neurons in the substantia nigra pars compacta. The etiology of PD remains unclear; however, generation of reactive oxygen species during oxidation of free dopamine (DA) in the cytoplasm might be one of the causes of selective dopaminergic neuron loss in PD. Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals take up and partition DA from neuronal cytoplasm into synaptic vesicles. Alterations of VMAT2 function might therefore cause cytoplasmic accumulation of free DA, which is toxic for dopaminergic neurons. We showed that dopaminergic neurons from VMAT2 heterozygous knockout mice were more vulnerable to the toxic effect of L-3, 4-dihydroxyphenylalanine (L-DOPA, a DA precursor) than those from wild-type mice. Our results suggest that reduction of VMAT2 activity might attenuate the efficacy of L-DOPA therapy for patients with PD.
Kariya
Shingo
S
Department of Neurology, Nara Medical University, Nara, Japan. neurology@yahoo.co.jp
Takahashi
Nobuyuki
N
Hirano
Makito
M
Ueno
Satoshi
S
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D007980:Levodopa / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
D000978:Antiparkinson Agents; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine