The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea.
The striatum harbours a population of dopaminergic neurons that is thought to act as a local source of dopamine (DA). This neuronal population increases in size in animal models of Parkinson's disease, where striatal DA levels are low, but its fate in idiopathic Parkinson's disease and Huntington's chorea is poorly known. In this study, we used antibodies raised against the enzyme tyrosine hydroxylase (TH), a faithful marker of dopaminergic neurons, to compare, by means of stereological counting methods, the number of striatal TH+ neurons on post-mortem brain sections from Parkinson's disease patients, Huntington's disease patients and age-matched controls. Propidium iodide nuclear staining was also performed to avoid counting short TH+ axonal segments that bear a large swollen varicosity and resemble small bipolar neurons. In normal subjects, TH+ neurons were scattered throughout the striatum, but they abounded preferentially in the ventral portion of the structure and were more numerous in the putamen than in the caudate nucleus. They displayed a multipolar cell body of medium size (10-20 mum in diameter) that emitted 3-5 smooth dendrites, a typical characteristic of striatal interneurons. These TH+ cells were rarely found in the small TH-poor striosomes, most of them being embedded in the large TH-rich extrastriosomal matrix. The number of striatal TH+ neurons was also found to vary according to an inverse relation with the age of the subjects. In pathological brains, the morphological characteristics of the striatal TH+ neurons were relatively unaltered, but the number of such neurons was markedly reduced compared with controls. The striatum of Parkinson's disease patients was found to contain six times less TH+ neurons than that of controls, whereas the striatum of Huntington's disease patients was largely devoid of such neurons. These findings are at odds with the results obtained in rodent and monkey models of Parkinson's disease, in which the number of striatal TH+ neurons is reported to increase markedly following DA denervation. Since Parkinson's disease patients examined in this study were all treated with l-3,4-dihydroxyphenylalanine to compensate for the loss of striatal DA and that levels of striatal DA are reportedly higher in the striatum of Huntington's disease patients compared with controls, we hypothesize that local DA concentrations exert a negative feedback on the expression of TH phenotype by striatal interneurons. A better knowledge of factors governing the in vivo state of this ectopic neuronal population could open new therapeutic avenues for the treatment of Parkinson's disease and Huntington's chorea.
Huot
Philippe
P
Centre de Recherche Université, Laval Robert-Giffard, Québec, QC, Canada G1J 1Z4.
Lévesque
Martin
M
Parent
André
A
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D002102:Cadaver; D002421:Caudate Nucleus / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D048429:Cell Size; D003342:Corpus Striatum / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D007395:Interneurons / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D011699:Putamen / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D015415:Biomarkers; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine