z-logo
Premium
Dopamine D 2 receptor knockout mice develop features of Parkinson disease
Author(s) -
Tinsley Rogan B.,
Bye Chris R.,
Parish Clare L.,
TziotisVais Angela,
George Sonia,
Culvenor Janetta G.,
Li QiaoXin,
Masters Colin L.,
Finkelstein David I.,
Horne Malcolm K.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21716
Subject(s) - pars compacta , substantia nigra , dopamine , striatum , dopaminergic , biology , neurodegeneration , cytoplasmic inclusion , microbiology and biotechnology , medicine , endocrinology , neuroscience , cytoplasm , disease
Objective This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic α‐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 α‐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 α‐synuclein immunoreactivity in SNpc neurons increased with age in both wild‐type and D 2 R(−/−) mice, most likely because of redistribution of α‐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. Interpretation 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. Ann Neurol 2009;66:472–484

This content is not available in your region!

Continue researching here.

Having issues? You can contact us here