TY - JOUR
T1 - Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice
AU - Salvatore, Michael F.
AU - Fisher, Brent
AU - Surgener, Stewart P.
AU - Gerhardt, Greg A.
AU - Rouault, Tracey
N1 - Funding Information:
Why would lack of translational regulator for ferritin cause damage to DA neurons? We suggest that functional iron deficiency may cause death of the sensitive dopaminergic cells of the SN. Recently, evaluation of an anemia that IRP-2 −/− mice develop revealed that the developing erythroblasts lack sufficient TfR to support heme synthesis [2] . The bone marrow of IRP-2 −/− animals visibly lacks iron. A different situation occurs in the brain where we observe an increase in ferric iron, which is most likely sequestered in ferritin. We suggest that neurons are functionally iron-deficient because they cannot take up sufficient iron through TfR and they inappropriately sequester iron in ferritin. Since TH requires iron for function, TH enzymatic activity may decrease, and this possibility is supported by recent evidence [21] . The increase in Ser40 phosphorylation may counteract the decrease in availability of essential iron. Since dopaminergic cells are unusually sensitive to various stresses, they may die or be senescent from iron deficiency, which could in turn lead to decreases in decreased levels of the dopaminergic proteins TH, DAT, and VMAT.
PY - 2005/10/3
Y1 - 2005/10/3
N2 - Abnormal iron accumulations are frequently observed in the brains of patients with Parkinson's disease and in normal aging. Iron metabolism is regulated in the CNS by iron regulatory proteins (IRP-1 and IRP-2). Mice engineered to lack IRP-2 develop abnormal motoric behaviors including tremors at rest, abnormal gait, and bradykinesia at middle to late age (18 to 24 months). To further characterize the dopamine (DA) systems of IRP-2 -/- mice, we harvested CNS tissue from age-matched wild type and IRP-2 -/- (16-19 months) and analyzed the protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), and DA levels in dorsal striatum, ventral striatum (including the core and shell of nucleus accumbens), and midbrain. We further analyzed the phosphorylation of TH in striatum at serine 40, serine 31, and serine 19. In both dorsal and ventral striatum of IRP-2 knockout mice, there was a 20-25% loss of TH protein and accompanied by a ∼50% increase in serine 40 phosphorylation above wild-type levels. No change in serine 31 phosphorylation was observed. In the ventral striatum, there was also a significant loss (∼40%) of DAT and VMAT2. Levels of DA were decreased (∼20%) in dorsal striatum, but turnover of DA was also elevated (∼30%) in dorsal striatum of IRP-2 -/- mice. We conclude that iron misregulation associated with the loss of IRP-2 protein affects DA regulation in the striatum. However, the modest loss of DA and DA-regulating proteins does not reflect the pathology of PD or animal models of PD. Instead, these observations support that the IRP-2 -/- genotype may enable neurobiological events associated with aging.
AB - Abnormal iron accumulations are frequently observed in the brains of patients with Parkinson's disease and in normal aging. Iron metabolism is regulated in the CNS by iron regulatory proteins (IRP-1 and IRP-2). Mice engineered to lack IRP-2 develop abnormal motoric behaviors including tremors at rest, abnormal gait, and bradykinesia at middle to late age (18 to 24 months). To further characterize the dopamine (DA) systems of IRP-2 -/- mice, we harvested CNS tissue from age-matched wild type and IRP-2 -/- (16-19 months) and analyzed the protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), and DA levels in dorsal striatum, ventral striatum (including the core and shell of nucleus accumbens), and midbrain. We further analyzed the phosphorylation of TH in striatum at serine 40, serine 31, and serine 19. In both dorsal and ventral striatum of IRP-2 knockout mice, there was a 20-25% loss of TH protein and accompanied by a ∼50% increase in serine 40 phosphorylation above wild-type levels. No change in serine 31 phosphorylation was observed. In the ventral striatum, there was also a significant loss (∼40%) of DAT and VMAT2. Levels of DA were decreased (∼20%) in dorsal striatum, but turnover of DA was also elevated (∼30%) in dorsal striatum of IRP-2 -/- mice. We conclude that iron misregulation associated with the loss of IRP-2 protein affects DA regulation in the striatum. However, the modest loss of DA and DA-regulating proteins does not reflect the pathology of PD or animal models of PD. Instead, these observations support that the IRP-2 -/- genotype may enable neurobiological events associated with aging.
KW - Dopamine
KW - IRP-2
KW - Iron metabolism
KW - Striatum
KW - Tyrosine hydroxylase
UR - http://www.scopus.com/inward/record.url?scp=24944457215&partnerID=8YFLogxK
U2 - 10.1016/j.molbrainres.2005.06.002
DO - 10.1016/j.molbrainres.2005.06.002
M3 - Article
C2 - 16051392
AN - SCOPUS:24944457215
VL - 139
SP - 341
EP - 347
JO - Molecular Brain Research
JF - Molecular Brain Research
SN - 0169-328X
IS - 2
ER -