Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice.
The growing body of evidence suggests that intermediate products of alpha-synuclein aggregation cause death of sensitive populations of neurones, particularly dopaminergic neurones, which is a critical event in the development of Parkinson's disease and other synucleinopathies. The role of two other members of the family, beta-synuclein and gamma-synuclein, in neurodegeneration is less understood. We studied the effect of inactivation of gamma-synuclein gene on mouse midbrain dopaminergic neurones. Reduced number of dopaminergic neurones was found in substantia nigra pars compacta (SNpc) but not in ventral tegmental area (VTA) of early post-natal and adult gamma-synuclein null mutant mice. Similar reductions were revealed in alpha-synuclein and double alpha-synuclein/gamma-synuclein null mutant animals. However, in none of these mutants did this lead to significant changes of striatal dopamine or dopamine metabolite levels and motor dysfunction. In all three studied types of null mutants, dopaminergic neurones of SNpc were resistant to methyl-phenyl-tetrahydropyridine (MPTP) toxicity. We propose that both synucleins are important for effective survival of SNpc neurones during critical period of development but, in the absence of these proteins, permanent activation of compensatory mechanisms allow many neurones to survive and become resistant to certain toxic insults.
Robertson
Darren C
DC
Department of Preclinical Veterinary Sciences, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Scotland, UK.
Schmidt
Oliver
O
Ninkina
Natalia
N
Jones
Paul A
PA
Sharkey
John
J
Buchman
Vladimir L
VL
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D002451:Cell Compartmentation; D002452:Cell Count; D003423:Critical Period, Psychological; D004351:Drug Resistance / Q000235:genetics*; D020267:MPTP Poisoning / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013378:Substantia Nigra / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein
D009419:Nerve Tissue Proteins; C497605:Snca protein, mouse; C497608:Sncb protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine