Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons.
Septin 5, a parkin substrate, is a vesicle- and membrane-associated protein that plays a significant role in inhibiting exocytosis. The regulatory function of Septin 5 in dopaminergic (DAergic) neurons of substantia nigra (SN), maintained at relatively low levels, has not yet been delineated. As loss of function mutations of parkin are the principal cause of a familial Parkinson's disease, a prevailing hypothesis is that the loss of parkin activity results in accumulation of Septin 5 which confers neuron-specific toxicity in SN-DAergic neurons. In vitro and in vivo models were used to support this hypothesis. In our well-characterized DAergic SN4741 cell model, acute accumulation of elevated levels of Septin 5, but not synphilin-1 (another parkin substrate), resulted in cytotoxic cell death that was markedly reduced by parkin co-transfection. A transgenic mouse model expressing a dominant negative parkin mutant accumulated moderate levels of Septin 5 in SN-DAergic neurons. These mice acquired a progressive l-DOPA responsive motor dysfunction that developed despite a 25% higher than normal level of striatal dopamine (DA) and no apparent loss of DAergic neurons. The phenotype of this animal, increased striatal dopamine and reduced motor function, was similar to that observed in parkin knockout animals, suggesting a common DAergic alteration. These data suggest that a threshold level of Septin 5 accumulation is required for DAergic cell loss and that l-DOPA-responsive motor deficits can occur even in the presence of elevated DA.
Son
Jin H
JH
Laboratory of Molecular Neurobiology, The W. M. Burke Medical Research Institute, White Plains, New York 10605, USA. hjson@med.cornell.edu
Kawamata
Hibiki
H
Yoo
Myung S
MS
Kim
Dae J
DJ
Lee
Young K
YK
Kim
Sooyoul
S
Dawson
Ted M
TM
Zhang
Hui
H
Sulzer
David
D
Yang
Lichuan
L
Beal
M Flint
MF
Degiorgio
Lorraine A
LA
Chun
Hong S
HS
Baker
Harriet
H
Peng
Chu
C
D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005799:Genes, Dominant; D047468:Immunoprecipitation; D007980:Levodopa / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism*; D058112:Septins; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D014018:Tissue Distribution; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D015259:Dopamine Agents; D009498:Neurotoxins; D007980:Levodopa; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C491612:Sept5 protein, mouse; D058112:Septins; D004298:Dopamine