The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway.
Toxic organic cations can damage nigrostriatal dopaminergic pathways as seen in most parkinsonian syndromes and in some cases of illicit drug exposure. Here, we show that the organic cation transporter 3 (Oct3) is expressed in nondopaminergic cells adjacent to both the soma and terminals of midbrain dopaminergic neurons. We hypothesized that Oct3 contributes to the dopaminergic damage by bidirectionally regulating the local bioavailability of toxic species. Consistent with this view, Oct3 deletion and pharmacological inhibition hampers the release of the toxic organic cation 1-methyl-4-phenylpyridinium from astrocytes and protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration in mice. Furthermore, Oct3 deletion impairs the removal of the excess extracellular dopamine induced by methamphetamine and enhances striatal dopaminergic terminal damage caused by this psychostimulant. These results may have far-reaching implications for our understanding of the mechanism of cell death in a wide range of neurodegenerative diseases and may open new avenues for neuroprotective intervention.
Cui
Mei
M
Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
Aras
Radha
R
Christian
Whitney V
WV
Rappold
Phillip M
PM
Hatwar
Mamata
M
Panza
Joseph
J
Jackson-Lewis
Vernice
V
Javitch
Jonathan A
JA
Ballatori
Nazzareno
N
Przedborski
Serge
S
Tieu
Kim
K
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism*; D013997:Time Factors; D000099254:Organic Cation Transporter 3
D004298:Dopamine; D018698:Glutamic Acid; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3