The mouse MPTP model: gene expression changes in dopaminergic neurons.
Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Although valuable animal models have been developed, our knowledge of the aetiology and pathogenic factors implicated in PD is still insufficient to develop causal therapeutic strategies aimed at halting its progression. The neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most valuable models for analysing pathological aspects of PD. In this paper we studied the gene expression patterns underlying the pathogenesis of MPTP-induced neurodegeneration. We treated young and old C57BL/6 mice with different schedules of MPTP to induce degenerative processes that vary in intensity and time-course. During the first week after intoxication we used nonradioactive in situ-hybridization to investigate the expression patterns of genes associated with (i) dopamine metabolism and signalling; (ii) familial forms of PD; (iii) protein folding and (iv) energy metabolism. MPTP injections induced different severities of neuronal injury depending on the age of the animals and the schedule of administration as well as a significant degeneration in the striatum. In situ hybridization showed that MPTP intoxication initiated a number of gene expression changes that (i) were restricted to the neurons of the substantia nigra pars compacta; (ii) were correlated in intensity and number of changes with the age of the animals and the severity of histopathological disturbances; (iii) displayed in each a significant down-regulation by the end of one week after the last MPTP injection, but (iv) varied within one MPTP regimen in expression levels during the observation period. The subacute injection of MPTP into one-year-old mice induced the most severe changes in gene expression. All genes investigated were affected. However, alpha-synuclein was the only gene that was exclusively up-regulated in MPTP-treated animals displaying cell death.
Kühn
Kati
K
Department of Animal Physiology, Ruhr-University of Bochum, D-44780 Bochum Biofrontera Pharmaceuticals AG, D-51377 Leverkusen, Germany.
Wellen
Jennifer
J
Link
Nina
N
Maskri
Lyutha
L
Lübbert
Hermann
H
Stichel
Christine C
CC
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004334:Drug Administration Schedule; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008025:Ligases / Q000378:metabolism; D020267:MPTP Poisoning; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009245:NADH Dehydrogenase / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism*; D051843:Synucleins; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein
D050483:Dopamine Plasma Membrane Transport Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C098483:NADH dehydrogenase subunit 4; D009419:Nerve Tissue Proteins; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D009245:NADH Dehydrogenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D017493:Leukocyte Common Antigens; D008025:Ligases; D004298:Dopamine