l-DOPA-induced dyskinesia is associated with a deficient numerical downregulation of striatal tyrosine hydroxylase mRNA-expressing neurons.
l-3,4-Dihydroxyphenylalanine (l-DOPA) is the therapeutic gold standard in Parkinson's disease. However, most patients develop debilitating abnormal involuntary movements termed l-DOPA-induced dyskinesia (LID) as therapy-complicating side effects. The underlying mechanisms of LID pathogenesis are still not fully understood. Recent evidence suggests an involvement of striatal tyrosine hydroxylase (TH) protein-expressing neurons, as they are capable of endogenously producing l-DOPA and possibly dopamine. The aim of this study was to elucidate changes of TH transcription in the striatum and nucleus accumbens that occur under experimental conditions of LID. Mice with a unilateral 6-hydroxydopamine-induced lesion of the medial forebrain bundle were treated daily with l-DOPA for 15days to provoke dyskinesia. In situ hybridization analysis revealed a significant numerical decrease of TH mRNA-positive neurons in the striatum and nucleus accumbens of mice not exhibiting LID, whereas dyskinetic animals failed to show this reduction of TH transcription. Interestingly, similar changes were observed in intact non-deafferentiated striata, demonstrating an l-DOPA-responsive transcriptional TH regulation independently from nigrostriatal lesion severity. Consolidation with our previous study on TH protein level (Keber et al., 2015) impressively highlights that LID is associated with both a deficient downregulation of TH transcription and an excessive translation of TH protein in intrastriatal neurons. As TH protein levels in comparison to mRNA levels showed a stronger correlation with development and severity of LID, antidyskinetic treatment strategies should focus on translational and posttranslational modulations of TH as a promising target.
Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany; Experimental Neurology, Department of Neurology, Philipps University, Marburg, Germany.
Martin
M
Klietz
Experimental Neurology, Department of Neurology, Philipps University, Marburg, Germany.
Ursula
U
Keber
Experimental Neurology, Department of Neurology, Philipps University, Marburg, Germany; Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Thomas
T
Carlsson
Experimental Neurology, Department of Neurology, Philipps University, Marburg, Germany.
Wei-Hua
WH
Chiu
Experimental Neurology, Department of Neurology, Philipps University, Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Günter U
GU
Höglinger
Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany.
Eberhard
E
Weihe
Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany. Electronic address: schaefem@staff.uni-marburg.de.
Martin K-H
MK
Schäfer
Experimental Neurology, Department of Neurology, Philipps University, Marburg, Germany. Electronic address: depboylu@med.uni-marburg.de.
Candan
C
Depboylu
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D004745:Enkephalins / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008474:Medial Forebrain Bundle; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D000978:Antiparkinson Agents; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; C029992:proenkephalin; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin; D014446:Tyrosine 3-Monooxygenase
Parkinson’s disease; abnormal involuntary movement; dopamine; in situ hybridization; nucleus accumbens; striatum