Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice

Margot Fournier, Amandine Roux, Jérôme Garrigue, Marie Paule Muriel, Paul Blanche, Hilal A. Lashuel, John P. Anderson, Robin Barbour, Jiping Huang, Sophie T. du Montcel, Alexis Brice, Olga Corti

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article number135
JournalBMC Neuroscience
Volume14
DOIs
Publication statusPublished - 5 Nov 2013
Externally publishedYes

Fingerprint

Synucleins
Transgenic Mice
Lewy Bodies
Mutation
Ubiquitin-Protein Ligases
Post Translational Protein Processing
Ubiquitin
Genes
Alleles
Neuropathology

Keywords

  • α-syn phosphorylation
  • α-syn truncation
  • parkin knockout mice
  • Parkinson's disease
  • Posttranslational modifications
  • Transgenic mice overproducing α-syn
  • Ubiquitin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neuroscience(all)

Cite this

Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice. / Fournier, Margot; Roux, Amandine; Garrigue, Jérôme; Muriel, Marie Paule; Blanche, Paul; Lashuel, Hilal A.; Anderson, John P.; Barbour, Robin; Huang, Jiping; du Montcel, Sophie T.; Brice, Alexis; Corti, Olga.

In: BMC Neuroscience, Vol. 14, 135, 05.11.2013.

Research output: Contribution to journalArticle

Fournier, M, Roux, A, Garrigue, J, Muriel, MP, Blanche, P, Lashuel, HA, Anderson, JP, Barbour, R, Huang, J, du Montcel, ST, Brice, A & Corti, O 2013, 'Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice', BMC Neuroscience, vol. 14, 135. https://doi.org/10.1186/1471-2202-14-135
Fournier, Margot ; Roux, Amandine ; Garrigue, Jérôme ; Muriel, Marie Paule ; Blanche, Paul ; Lashuel, Hilal A. ; Anderson, John P. ; Barbour, Robin ; Huang, Jiping ; du Montcel, Sophie T. ; Brice, Alexis ; Corti, Olga. / Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice. In: BMC Neuroscience. 2013 ; Vol. 14.
@article{4f83a80323e04d55a3c583487ec34b9e,
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.",
keywords = "α-syn phosphorylation, α-syn truncation, parkin knockout mice, Parkinson's disease, Posttranslational modifications, Transgenic mice overproducing α-syn, Ubiquitin",
author = "Margot Fournier and Amandine Roux and J{\'e}r{\^o}me Garrigue and Muriel, {Marie Paule} and Paul Blanche and Lashuel, {Hilal A.} and Anderson, {John P.} and Robin Barbour and Jiping Huang and {du Montcel}, {Sophie T.} and Alexis Brice and Olga Corti",
year = "2013",
month = "11",
day = "5",
doi = "10.1186/1471-2202-14-135",
language = "English",
volume = "14",
journal = "BMC Neuroscience",
issn = "1471-2202",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice

AU - Fournier, Margot

AU - Roux, Amandine

AU - Garrigue, Jérôme

AU - Muriel, Marie Paule

AU - Blanche, Paul

AU - Lashuel, Hilal A.

AU - Anderson, John P.

AU - Barbour, Robin

AU - Huang, Jiping

AU - du Montcel, Sophie T.

AU - Brice, Alexis

AU - Corti, Olga

PY - 2013/11/5

Y1 - 2013/11/5

N2 - 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.

AB - 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.

KW - α-syn phosphorylation

KW - α-syn truncation

KW - parkin knockout mice

KW - Parkinson's disease

KW - Posttranslational modifications

KW - Transgenic mice overproducing α-syn

KW - Ubiquitin

UR - http://www.scopus.com/inward/record.url?scp=84887033337&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887033337&partnerID=8YFLogxK

U2 - 10.1186/1471-2202-14-135

DO - 10.1186/1471-2202-14-135

M3 - Article

VL - 14

JO - BMC Neuroscience

JF - BMC Neuroscience

SN - 1471-2202

M1 - 135

ER -