Dopamine depletion induces distinct compensatory gene expression changes in DARPP-32 signal transduction cascades of striatonigral and striatopallidal neurons.
Functional alterations in striatal projection neurons play a critical role in the development of motor symptoms in Parkinson's disease (PD), but their molecular adaptation to dopamine depletion remains poorly understood. In particular, type and extent of regulation in postsynaptic signal transduction pathways that determine the responsiveness of striatal projection neurons to incoming stimuli, are currently unknown. Using cell-type-specific transcriptome analyses in a rodent model of chronic dopamine depletion, we identified large-scale gene expression changes, including neurotransmitter receptors, signal transduction cascades, and target proteins of dopamine signaling in striatonigral and striatopallidal neurons. Within the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) cascade of enzymes that plays a central role in signal integration of dopaminoceptive neurons multiple catalytic and regulatory subunits change their mRNA expression levels. In addition to the number of genes the fact that the alterations occur at multiple levels stresses the biological relevance of transcriptional regulation for adaptations of postsynaptic signaling pathways. The overall pattern of changes in both striatonigral and striatopallidal neurons is compatible with homeostatic mechanisms. In accordance with the distinct biological effects of dopamine D(1) and D(2) receptor stimulation, the alterations of the transcriptional profiles most likely result in prodopaminergic phosphorylation patterns. Our data provide insight into the disease-related plasticity of functional genomic networks in vivo that might contribute to the protracted preclinical phase of PD. In addition, the data have potential implications for the symptomatic treatment of the disease.
Meurers
Bernhard H
BH
Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA. bmeurers@ljmail.net
Dziewczapolski
Gustavo
G
Shi
Tao
T
Bittner
Anton
A
Kamme
Fredrik
F
Shults
Clifford W
CW
D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects; D004298:Dopamine / Q000172:deficiency*; D015259:Dopamine Agents / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D046228:Microarray Analysis; D042282:Microdissection / Q000379:methods; D009434:Neural Pathways / Q000293:injuries; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate / Q000378:metabolism
D018663:Adrenergic Agents; D015259:Dopamine Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D007473:Ion Channels; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate; D007980:Levodopa; D016627:Oxidopamine; D004298:Dopamine