Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy

Voluntary movement difficulties in Parkinson's disease are initially relieved by L-DOPA therapy, but with disease progression, the repeated L-DOPA treatments can produce debilitating motor abnormalities known as L-DOPA-induced dyskinesias. We show here that 2 striatum-enriched regulators of the...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (8), p.2892-2896
Main Authors: Crittenden, Jill R, Cantuti-Castelvetri, Ippolita, Saka, Esen, Keller-McGandy, Christine E, Hernandez, Ledia F, Kett, Lauren R, Young, Anne B, Standaert, David G, Graybiel, Ann M
Format: Article
Language:English
Subjects:
Animals
Antiparkinson Agents - adverse effects
Basal ganglia
Behavioral neuroscience
Biological Sciences
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Dyskinesia
Gene expression regulation
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - physiology
Immunohistochemistry
Lesions
Male
Medical treatment
Messenger RNA
Motor Activity
Neurons
Parkinson disease
Polymerase Chain Reaction
Rats
Rats, Sprague-Dawley
RNA, Messenger - genetics
Up regulation
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Summary:Voluntary movement difficulties in Parkinson's disease are initially relieved by L-DOPA therapy, but with disease progression, the repeated L-DOPA treatments can produce debilitating motor abnormalities known as L-DOPA-induced dyskinesias. We show here that 2 striatum-enriched regulators of the Ras/Rap/ERK MAP kinase signal transduction cascade, matrix-enriched CalDAG-GEFI and striosome-enriched CalDAG-GEFII (also known as RasGRP), are strongly and inversely dysregulated in proportion to the severity of abnormal movements induced by L-DOPA in a rat model of parkinsonism. In the dopamine-depleted striatum, the L-DOPA treatments produce down-regulation of CalDAG-GEFI and up-regulation of CalDAG-GEFII mRNAs and proteins, and quantification of the mRNA levels shows that these changes are closely correlated with the severity of the dyskinesias. As these CalDAG-GEFs control ERK cascades, which are implicated in L-DOPA-induced dyskinesias, and have differential compartmental expression patterns in the striatum, we suggest that they may be key molecules involved in the expression of the dyskinesias. They thus represent promising new therapeutic targets for limiting the motor complications induced by L-DOPA therapy.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0812822106