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 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.
Crittenden
Jill R
JR
Department of Brain and Cognitive Sciences and the McGovern Institute for Brain Research, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
Cantuti-Castelvetri
Ippolita
I
Saka
Esen
E
Keller-McGandy
Christine E
CE
Hernandez
Ledia F
LF
Kett
Lauren R
LR
Young
Anne B
AB
Standaert
David G
DG
Graybiel
Ann M
AM
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000978:Antiparkinson Agents; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; C491789:Rasgrp1 protein, rat