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Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons
Author(s) -
Son Jin H.,
Kawamata Hibiki,
Yoo Myung S.,
Kim Dae J.,
Lee Young K.,
Kim SooYoul,
Dawson Ted M.,
Zhang Hui,
Sulzer David,
Yang Lichuan,
Beal M. Flint,
DeGiorgio Lorraine A.,
Chun Hong S.,
Baker Harriet,
Peng Chu
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03257.x
Subject(s) - septin , parkin , dopaminergic , dopamine , biology , neurotoxicity , microbiology and biotechnology , substantia nigra , neuroscience , parkinson's disease , medicine , toxicity , biochemistry , cell , cytokinesis , disease , cell division
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.