Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy

Margot Fournier, Jérémie Vitte, Jérôme Garrigue, Dominique Langui, Jean Philippe Dullin, Françoise Saurini, Naïma Hanoun, Fernando Perez-Diaz, Fabien Cornilleau, Chantal Joubert, Héctor Ardila-Osorio, Sabine Traver, René Duchateau, Cécile Goujet-Zalc, Katerina Paleologou, Hilal A. Lashuel, Christian Haass, Charles Duyckaerts, Charles Cohen-Salmon, Philipp J. Kahle & 3 others Michel Hamon, Alexis Brice, Olga Corti

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

In synucleinopathies, including Parkinson's disease, partially ubiquitylated α-synuclein species phosphorylated on serine 129 (PS129-α-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against α-synuclein-mediated toxicity in various models. We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and a-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of PS129-α-synuclein but not PS87-α-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the PS129-α-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with PS129-α-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin-and PS129-α-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of PS129-α-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human α-synuclein were significantly delayed in Parkin-deficient mice. These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.

Original languageEnglish
Article numbere6629
JournalPLoS One
Volume4
Issue number8
DOIs
Publication statusPublished - 14 Aug 2009
Externally publishedYes

Fingerprint

Synucleins
disease models
ubiquitin
neurons
animal models
mice
caspase-9
ubiquitin-protein ligase
neurites
Parkinson disease
neurodegenerative diseases
brain stem
spinal cord
serine
signs and symptoms (animals and humans)
biochemical pathways
Ubiquitin
toxicity
phenotype
antibodies

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Fournier, M., Vitte, J., Garrigue, J., Langui, D., Dullin, J. P., Saurini, F., ... Corti, O. (2009). Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy. PLoS One, 4(8), [e6629]. https://doi.org/10.1371/journal.pone.0006629

Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy. / Fournier, Margot; Vitte, Jérémie; Garrigue, Jérôme; Langui, Dominique; Dullin, Jean Philippe; Saurini, Françoise; Hanoun, Naïma; Perez-Diaz, Fernando; Cornilleau, Fabien; Joubert, Chantal; Ardila-Osorio, Héctor; Traver, Sabine; Duchateau, René; Goujet-Zalc, Cécile; Paleologou, Katerina; Lashuel, Hilal A.; Haass, Christian; Duyckaerts, Charles; Cohen-Salmon, Charles; Kahle, Philipp J.; Hamon, Michel; Brice, Alexis; Corti, Olga.

In: PLoS One, Vol. 4, No. 8, e6629, 14.08.2009.

Research output: Contribution to journalArticle

Fournier, M, Vitte, J, Garrigue, J, Langui, D, Dullin, JP, Saurini, F, Hanoun, N, Perez-Diaz, F, Cornilleau, F, Joubert, C, Ardila-Osorio, H, Traver, S, Duchateau, R, Goujet-Zalc, C, Paleologou, K, Lashuel, HA, Haass, C, Duyckaerts, C, Cohen-Salmon, C, Kahle, PJ, Hamon, M, Brice, A & Corti, O 2009, 'Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy', PLoS One, vol. 4, no. 8, e6629. https://doi.org/10.1371/journal.pone.0006629
Fournier, Margot ; Vitte, Jérémie ; Garrigue, Jérôme ; Langui, Dominique ; Dullin, Jean Philippe ; Saurini, Françoise ; Hanoun, Naïma ; Perez-Diaz, Fernando ; Cornilleau, Fabien ; Joubert, Chantal ; Ardila-Osorio, Héctor ; Traver, Sabine ; Duchateau, René ; Goujet-Zalc, Cécile ; Paleologou, Katerina ; Lashuel, Hilal A. ; Haass, Christian ; Duyckaerts, Charles ; Cohen-Salmon, Charles ; Kahle, Philipp J. ; Hamon, Michel ; Brice, Alexis ; Corti, Olga. / Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy. In: PLoS One. 2009 ; Vol. 4, No. 8.
@article{a8209373798b4da8b38fb8cc1f44ed0b,
title = "Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy",
abstract = "In synucleinopathies, including Parkinson's disease, partially ubiquitylated α-synuclein species phosphorylated on serine 129 (PS129-α-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against α-synuclein-mediated toxicity in various models. We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and a-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of PS129-α-synuclein but not PS87-α-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5{\%} of the PS129-α-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with PS129-α-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin-and PS129-α-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of PS129-α-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human α-synuclein were significantly delayed in Parkin-deficient mice. These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.",
author = "Margot Fournier and J{\'e}r{\'e}mie Vitte and J{\'e}r{\^o}me Garrigue and Dominique Langui and Dullin, {Jean Philippe} and Fran{\cc}oise Saurini and Na{\"i}ma Hanoun and Fernando Perez-Diaz and Fabien Cornilleau and Chantal Joubert and H{\'e}ctor Ardila-Osorio and Sabine Traver and Ren{\'e} Duchateau and C{\'e}cile Goujet-Zalc and Katerina Paleologou and Lashuel, {Hilal A.} and Christian Haass and Charles Duyckaerts and Charles Cohen-Salmon and Kahle, {Philipp J.} and Michel Hamon and Alexis Brice and Olga Corti",
year = "2009",
month = "8",
day = "14",
doi = "10.1371/journal.pone.0006629",
language = "English",
volume = "4",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy

AU - Fournier, Margot

AU - Vitte, Jérémie

AU - Garrigue, Jérôme

AU - Langui, Dominique

AU - Dullin, Jean Philippe

AU - Saurini, Françoise

AU - Hanoun, Naïma

AU - Perez-Diaz, Fernando

AU - Cornilleau, Fabien

AU - Joubert, Chantal

AU - Ardila-Osorio, Héctor

AU - Traver, Sabine

AU - Duchateau, René

AU - Goujet-Zalc, Cécile

AU - Paleologou, Katerina

AU - Lashuel, Hilal A.

AU - Haass, Christian

AU - Duyckaerts, Charles

AU - Cohen-Salmon, Charles

AU - Kahle, Philipp J.

AU - Hamon, Michel

AU - Brice, Alexis

AU - Corti, Olga

PY - 2009/8/14

Y1 - 2009/8/14

N2 - In synucleinopathies, including Parkinson's disease, partially ubiquitylated α-synuclein species phosphorylated on serine 129 (PS129-α-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against α-synuclein-mediated toxicity in various models. We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and a-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of PS129-α-synuclein but not PS87-α-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the PS129-α-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with PS129-α-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin-and PS129-α-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of PS129-α-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human α-synuclein were significantly delayed in Parkin-deficient mice. These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.

AB - In synucleinopathies, including Parkinson's disease, partially ubiquitylated α-synuclein species phosphorylated on serine 129 (PS129-α-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against α-synuclein-mediated toxicity in various models. We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and a-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of PS129-α-synuclein but not PS87-α-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the PS129-α-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with PS129-α-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin-and PS129-α-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of PS129-α-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human α-synuclein were significantly delayed in Parkin-deficient mice. These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.

UR - http://www.scopus.com/inward/record.url?scp=69949115593&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69949115593&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0006629

DO - 10.1371/journal.pone.0006629

M3 - Article

VL - 4

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e6629

ER -