title: Nigral overexpression of alpha-synuclein in the absence of parkin enhances alpha-synuclein phosphorylation but does not modulate dopaminergic neurodegeneration.
abstract: Alpha-synuclein is a key protein in the pathogenesis of Parkinson's disease. Mutations in the parkin gene are the most common cause of early-onset autosomal recessive Parkinson's disease, probably through a loss-of-function mechanism. However, the molecular mechanism by which loss of parkin function leads to the development of the disease and the role of alpha-synuclein in parkin-associated Parkinson's disease is still not elucidated. Conflicting results were reported about the effect of the absence of parkin on alpha-synuclein-mediated neurotoxicity using a transgenic approach. In this study, we investigated the effect of loss of parkin on alpha-synuclein neuropathology and toxicity in adult rodent brain using viral vectors. Therefore, we overexpressed human wild type alpha-synuclein in the substantia nigra of parkin knockout and wild type mice using two different doses of recombinant adeno-associated viral vectors.
  
  
  
  No difference was observed in nigral dopaminergic cell loss between the parkin knockout mice and wild type mice up to 16 weeks after viral vector injection. However, the level of alpha-synuclein phosphorylated at serine residue 129 in the substantia nigra was significantly increased in the parkin knockout mice compared to the wild type mice while the total expression level of alpha-synuclein was similar in both groups. The increased alpha-synuclein phosphorylation was confirmed in a parkin knockdown cell line.
  
  
  
  These findings support a functional relationship between parkin and alpha-synuclein phosphorylation in rodent brain.
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium. annexsophie.vanrompuy@uzleuven.be.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Van Rompuy
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium.
authors.forename: Marusela
authors.initials: M
authors.lastname: Oliveras-Salvá
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium. Anke.VanderPerren@med.kuleuven.be.
authors.forename: Anke
authors.initials: A
authors.lastname: Van der Perren
authors.affiliation: Inserm, U 975, CRICM, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France. olga.corti@upmc.fr.|UPMC Université Paris 06, UMR_S975, F-75013, Paris, France. olga.corti@upmc.fr.|CNRS, UMR 7225, F-75013, Paris, France. olga.corti@upmc.fr.
authors.forename: Olga
authors.initials: O
authors.lastname: Corti
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium. Chris.VanDenHaute@med.kuleuven.be.|Leuven Viral Vector Core, KU Leuven, 3000, Leuven, Belgium. Chris.VanDenHaute@med.kuleuven.be.
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium. Veerle.Baekelandt@med.kuleuven.be.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
mesh_terms: D000818:Animals; D002452:Cell Count; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D059290:Dopaminergic Neurons / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D009410:Nerve Degeneration; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D010768:Phosphoserine / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D051844:alpha-Synuclein; D010768:Phosphoserine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein