title: Septin 4, the drosophila ortholog of human CDCrel-1, accumulates in parkin mutant brains and is functionally related to the Nedd4 E3 ubiquitin ligase.
abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although most PD cases are sporadic, several loci have been involved in the disease. parkin (PARK) is causative of autosomal recessive juvenile Parkinsonism (ARJP) and encodes an E3 ubiquitin ligase associated with proteasomal degradation. It was proposed that loss of PARK function may lead to the toxic accumulation of its substrates in the brain, thus causing dopaminergic (DA) neuron death. Indeed, the first identified PARK substrate was CDCrel-1, a protein of the Septin family that accumulates in ARPJ brains. Drosophila has been used as a successful model organism to study PD broadly contributing to the understanding of the disease. Consistently, park mutant flies recapitulate some key features of ARJP patients. In this scenario, we previously reported that overexpression of Septin 4 (Sep4), the Drosophila ortholog of CDCrel-1, is toxic for DA neurons and interacts physically with Park, thus suggesting that Sep4 could be a Park substrate in Drosophila. Confirming this hypothesis, we show that Sep4 accumulates in park mutant brains as its human counterpart. Furthermore, we demonstrate that Nedd4, another E3 ubiquitin ligase that may have a role in PD, is functionally related to Sep4 and could be involved in regulating Sep4 subcellular localization/trafficking.
authors.affiliation: Departamento de Genética, Facultad de CC Biológicas, Universidad de Valencia, Dr. Moliner 50, Burjassot, 46100, Valencia, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Muñoz-Soriano
authors.forename: Rocío
authors.initials: R
authors.lastname: Nieto-Arellano
authors.forename: Nuria
authors.initials: N
authors.lastname: Paricio
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004331:Drosophila melanogaster; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D017952:Ganglia, Invertebrate / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D016296:Mutagenesis / Q000502:physiology; D000075702:Nedd4 Ubiquitin Protein Ligases; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D021381:Protein Transport / Q000502:physiology; D058112:Septins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014921:Wings, Animal / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; C109366:SEPTIN5 protein, human; C577173:Sep4 protein, Drosophila; D058112:Septins; C487430:park protein, Drosophila