Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism.
Progressive degeneration of nigrostriatal dopaminergic (DA-ergic) neurons is a key component in the pathogenesis of Parkinson's disease, which develops for a long time at the preclinical stage with no motor dysfunctions due to the initiation of compensatory processes. The goal of this study was to evaluate the changes in surviving nigrostriatal DA-ergic neurons with focus on tyrosine hydroxylase (TH) in MPTP-treated mice at the presymptomatic and early symptomatic stages of parkinsonism. According to our data, a partial degeneration of DA-ergic neurons at the presymptomatic stage was accompanied by: (i) no change in TH mRNA content in the substantia nigra (SN) suggesting a compensatory increase of TH gene expression in individual neurons; (ii) a decrease of TH protein content in the nigrostriatal system and no change in individual neurons, suggesting a slowdown of TH translation. When comparing DA-ergic neurons at the early symptomatic stage and presymptomatic stage, it becomes evident: (i) a decrease of TH mRNA content in the SN and hence gene expression in individual neurons; (ii) a decrease of TH content in the striatum and its increase in the SN and individual neurons suggesting an acceleration of TH translation. TH activity, an index of the rate of DA synthesis, was unchanged in the SN and decreased in the striatum to the same degree at both stages of parkinsonism. In the meantime, TH activity in individual neurons appeared to be compensatory increased, but to a higher degree at the symptomatic stage than at the presymptomatic one. These data first show that DA depletion, which provokes motor dysfunction, is not a result of the decrease of TH activity and the rate of DA synthesis but is rather related to either a decrease of DA release or an increase of DA uptake in striatal DA-ergic axons.
Laboratory of Hormonal Regulations, Institute of Developmental Biology RAS, Moscow, Russia; Laboratory of Neurohistology, Institute of Normal Physiology RAMS, Moscow, Russia.
Elena A
EA
Kozina
Laboratory of Hormonal Regulations, Institute of Developmental Biology RAS, Moscow, Russia; Laboratory of Neurohistology, Institute of Normal Physiology RAMS, Moscow, Russia.
Gulnara R
GR
Khakimova
Laboratory of Neurohistology, Institute of Normal Physiology RAMS, Moscow, Russia; IC2N, IBDML, UMR6216 CNRS-Université de la Méditerranée, Marseille, France.
Vitaly G
VG
Khaindrava
Laboratory of General Pathophysiology of Nervous System, Institute of General Pathology and Pathological Physiology, RAMS, Moscow, Russia.
Valeriayn G
VG
Kucheryanu
Laboratory of Gene Expression Regulation, Institute of Gene Biology RAS, Moscow, Russia.
Nadezhda E
NE
Vorobyeva
Laboratory of Gene Expression Regulation, Institute of Gene Biology RAS, Moscow, Russia.
Alexey N
AN
Krasnov
Laboratory of Gene Expression Regulation, Institute of Gene Biology RAS, Moscow, Russia.
Sophia G
SG
Georgieva
IC2N, IBDML, UMR6216 CNRS-Université de la Méditerranée, Marseille, France.
Lidiya
L
Kerkerian-Le Goff
Laboratory of Hormonal Regulations, Institute of Developmental Biology RAS, Moscow, Russia; Laboratory of Neurohistology, Institute of Normal Physiology RAMS, Moscow, Russia. Electronic address: michael.ugrumov@mail.ru.
Michael V
MV
Ugrumov
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors / Q000494:pharmacology; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D004563:Electrochemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D007980:Levodopa / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D006834:Hydrazines; D012333:RNA, Messenger; D007980:Levodopa; C004297:3-hydroxybenzylhydrazine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Dopamine; Mice; Nigrostriatal system; Parkinson's disease; Tyrosine hydroxylase