Dopamine D2 receptor knockout mice develop features of Parkinson disease.
OBJECTIVE
This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic alpha-synuclein-containing cytoplasmic inclusion of Parkinson disease (PD).


METHODS
Mice with targeted deletion of the dopamine D(2) receptor gene (D(2)R[-/-]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy.


RESULTS
LB-like cytoplasmic inclusions containing alpha-synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D(2)R(-/-) mice, and were also occasionally seen in aged wild-type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic alpha-synuclein immunoreactivity in SNpc neurons increased with age in both wild-type and D(2)R(-/-) mice, most likely because of redistribution of alpha-synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D(2)R(-/-) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc.


CONCLUSIONS
Increased sprouting and DA turnover, as observed in PD and D(2)R(-/-) mice, augments LB-like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy.
Tinsley
Rogan B
RB
Howard Florey Institute, the University of Melbourne, Parkville, Australia.
Bye
Chris R
CR
Parish
Clare L
CL
Tziotis-Vais
Angela
A
George
Sonia
S
Culvenor
Janetta G
JG
Li
Qiao-Xin
QX
Masters
Colin L
CL
Finkelstein
David I
DI
Horne
Malcolm K
MK
D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051844:alpha-Synuclein / Q000378:metabolism
D017448:Receptors, Dopamine D2; D051844:alpha-Synuclein