Zeevalk, G. D., L. P. Bernard, et al. (2001). "Differential
sensitivity of mesencephalic neurons to inhibition of phosphatase 2A." J
Pharmacol Exp Ther 298(3): 925-33.
Disturbance in phosphorylation/dephosphorylation can trigger apoptosis. Little
is known as to its effects on mesencephalic dopamine neurons, the major neurons
lost in Parkinson's disease. In this study, okadaic acid (OKA), a phosphatase 1
and 2A inhibitor, with greater potency toward 2A, was toxic to mesencephalic
dopamine and gamma-aminobutyric acid (GABA) neurons, however, dopamine neurons
were 4-fold more sensitive. The EC(50) for dopamine versus GABA toxicity was 1.5
versus 6.5 nM, respectively, and was consistent with an inhibition of
phosphatase 2A. Dopamine neurons were also more sensitive to calyculin-A, a
phosphatase inhibitor equipotent toward 1 and 2A. OKA-methyl-ester, which lacks
phosphatase inhibitory activity, was without effect. DNA laddering typical of
apoptosis was observed in cultures at a concentration that was specifically
toxic to dopamine neurons (5 nM). In contrast to the sensitivity of
mesencephalic neurons to phosphatase inhibition, inhibition of protein kinase
activity with staurosporine or K252a showed little toxicity and protected
neurons from OKA. Consistent with in vitro findings, infusion of 32 to 320 pmol
of OKA into the left striatum of rats caused a dose-dependent loss of striatal
dopamine without any loss of GABA 1 week following infusion. Acutely, OKA
increased tyrosine hydroxylase activity, a phosphatase 2A substrate, and
increased dopamine turnover. The above-mentioned findings demonstrate that
dysregulation of phosphatase activity is detrimental to mesencephalic neurons,
with dopamine neurons, in vitro and in vivo, being relatively more sensitive to
phosphatase 2A inhibition. Disturbances in the phosphorylation control of
proteins unique to dopamine neurons may contribute to their enhanced
vulnerability to OKA exposure.
Zhao, W. Q., L. Latinwo, et al. (2001). "L-dopa upregulates the expression and
activities of methionine adenosyl transferase and catechol-O-methyltransferase."
Exp Neurol 171(1): 127-38.
High nonphysiological doses of l-dopa are administered to Parkinson's disease
(PD) patients, to replenish the depleted dopamine (DA). A large portion of the
administered L-dopa and the newly formed DA undergoes methylation by reacting
with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and
DA, is utilized and great demands are placed on the transmethylation system. In
this study we investigated whether L-dopa increases the transmethylation process
by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM,
and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl
group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa,
four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine
(SAH), MAT, and COMT were measured following a 24-h withdrawal period. An
increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to
about 164% of control. The brain level of 3-OMD increased to 870% of the
control. SAM was increased by 44% after the sixth day and SAH level was about
double after the second day. After day 3, MAT activity was increased by about
35%. Western blot analysis showed that MAT is more clearly characterized in 10%
mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa
(alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa
and, more prominently, the 48-kDa subunits of MAT and the potential
transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa
subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands
in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the
dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the
brain by day 6 and peaked on day 9. The highlight of the study is the fact that
L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA
after the sixth day coincides with the increase in SAM and the 48-kDa MAT
protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is
likely to occur and in turn increase the methylation and reduction of L-dopa and
DA that may help cause the tolerance or the wearing-off effect developed to
L-dopa.
Zhou, B., S. K. Westaway, et al. (2001). "A novel pantothenate kinase gene
(PANK2) is defective in Hallervorden-Spatz syndrome." Nat Genet 28(4):
345-9.
Hallervorden-Spatz syndrome (HSS) is an autosomal recessive neurodegenerative
disorder associated with iron accumulation in the brain. Clinical features
include extrapyramidal dysfunction, onset in childhood, and a relentlessly
progressive course. Histologic study reveals iron deposits in the basal ganglia.
In this respect, HSS may serve as a model for complex neurodegenerative
diseases, such as Parkinson disease, Alzheimer disease, Huntington disease and
human immunodeficiency virus (HIV) encephalopathy, in which pathologic
accumulation of iron in the brain is also observed. Thus, understanding the
biochemical defect in HSS may provide key insights into the regulation of iron
metabolism and its perturbation in this and other neurodegenerative diseases.
Here we show that HSS is caused by a defect in a novel pantothenate kinase gene
and propose a mechanism for oxidative stress in the pathophysiology of the
disease.