Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice.
The role of dopamine as a vulnerability factor and a toxic agent in Parkinson's disease (PD) is still controversial, yet the presumed dopamine toxicity is partly responsible for the "DOPA-sparing" clinical practice that avoids using L-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, in early PD. There is a lack of studies on animal models that directly isolate dopamine as one determining factor in causing neurodegeneration. To address this, we have generated a novel transgenic mouse model in which striatal neurons are engineered to take up extracellular dopamine without acquiring regulatory mechanisms found in dopamine neurons. These mice developed motor dysfunctions and progressive neurodegeneration in the striatum within weeks. The neurodegeneration was accompanied by oxidative stress, evidenced by substantial oxidative protein modifications and decrease in glutathione. Ultrastructural morphologies of degenerative cells suggest necrotic neurodegeneration. Moreover, L-DOPA accelerated neurodegeneration and worsened motor dysfunction. In contrast, reducing dopamine input to striatum by lesioning the medial forebrain bundle attenuated motor dysfunction. These data suggest that pathology in genetically modified striatal neurons depends on their dopamine supply. These neurons were also supersensitive to neurotoxin. A very low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5 mg/kg) caused profound neurodegeneration of striatal neurons, but not midbrain dopamine neurons. Our results provide the first in vivo evidence that chronic exposure to unregulated cytosolic dopamine alone is sufficient to cause neurodegeneration. The present study has significant clinical implications, because dopamine replacement therapy is the mainstay of PD treatment. In addition, our model provides an efficient in vivo approach to test therapeutic agents for PD.
Chen
Linan
L
Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA. lichen@bsd.uchicago.edu
Ding
Yunmin
Y
Cagniard
Barbara
B
Van Laar
Amber D
AD
Mortimer
Amanda
A
Chi
Wanhao
W
Hastings
Teresa G
TG
Kang
Un Jung
UJ
Zhuang
Xiaoxi
X
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D015259:Dopamine Agents / Q000008:administration & dosage; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004318:Doxycycline / Q000008:administration & dosage; D007839:Functional Laterality; D007980:Levodopa / Q000008:administration & dosage; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology*; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016548:Prosencephalon / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D011597:Psychomotor Performance / Q000502:physiology; D016622:Silver Staining / Q000379:methods
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009498:Neurotoxins; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517675:Camk2a protein, rat; D004318:Doxycycline; D004298:Dopamine