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Overexpression of Septin 4, the Drosophila homologue of human CDCrel‐1, is toxic for dopaminergic neurons
Author(s) -
MuñozSoriano Verónica,
Paricio Nuria
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05937.x
Subject(s) - parkin , ubiquitin ligase , septin , biology , ubiquitin , dopaminergic , microbiology and biotechnology , genetics , phenotype , mutant , proteasome , parkinsonism , mutation , loss function , gene , parkinson's disease , dopamine , neuroscience , cytokinesis , medicine , cell division , disease , cell
parkin loss‐of‐function mutations are linked to autosomal recessive juvenile parkinsonism. Parkin is an E3 ubiquitin ligase that promotes degradation of specific target proteins by the proteasome. It has been proposed that loss of Parkin activity will result in accumulation of its substrates, thus leading to dopaminergic (DA) neuron death. In Drosophila, parkin mutations cause degeneration of a subset of DA neurons in the brain but no Parkin substrates have yet been described. Here we characterized the septin 4 gene, which encodes the Drosophila orthologue of human CDCrel‐1, a Parkin substrate. We showed that Septin 4 overexpression causes age‐dependent disruption of DA neuron integrity in the dorsomedial cluster, which is suppressed by coexpression of Parkin and enhanced by reducing parkin function. Furthermore, other phenotypes caused by Septin 4 overexpression are also enhanced in a heterozygous parkin mutant background. This indicates that Septin 4 accumulation is toxic for DA neurons and suggests that Septin 4 could be a genuine substrate of Drosophila Parkin. Regarding this, we also showed that both proteins are able to interact physically with each other in vitro , thus supporting this hypothesis.