title: Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice.
abstract: BACKGROUND
  Mutations of the gene encoding the major component of Lewy bodies (LB), α-synuclein (α-syn), cause autosomal dominant forms of Parkinson's disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against α-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human α-syn (hA30Pα-syn) and with two, one or no parkin knockout alleles.
  
  
  RESULTS
  Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to α-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar α-syn species phosphorylated at S129 (PS129α-syn) were the predominant neuropathological feature in hA30Pα-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and α-syn truncated at D135 (α-synD135), indicating that PS129α-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction.
  
  
  CONCLUSIONS
  These findings suggest that Parkin deficiency acts as a protective modifier in α-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of α-syn deposits in end-stage disease.
authors.forename: Margot
authors.initials: M
authors.lastname: Fournier
authors.forename: Amandine
authors.initials: A
authors.lastname: Roux
authors.forename: Jérôme
authors.initials: J
authors.lastname: Garrigue
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Muriel
authors.forename: Paul
authors.initials: P
authors.lastname: Blanche
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
authors.forename: John P
authors.initials: JP
authors.lastname: Anderson
authors.forename: Robin
authors.initials: R
authors.lastname: Barbour
authors.forename: Jiping
authors.initials: J
authors.lastname: Huang
authors.forename: Sophie Tezenas
authors.initials: ST
authors.lastname: du Montcel
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Inserm, U 975, CRICM, Hôpital de la Pitié-Salpêtrière, F-75013 Paris, France. olga.corti@upmc.fr.
authors.forename: Olga
authors.initials: O
authors.lastname: Corti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009048:Motor Skills; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein