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. KahleMichel Hamon, Alexis Brice, Olga Corti

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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

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ASJC Scopus subject areas

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

Cite this

Fournier, M., Vitte, J., Garrigue, J., Langui, D., Dullin, J. P., Saurini, F., Hanoun, N., Perez-Diaz, F., Cornilleau, F., Joubert, C., Ardila-Osorio, H., Traver, S., Duchateau, R., Goujet-Zalc, C., Paleologou, K., Lashuel, H. A., Haass, C., Duyckaerts, C., Cohen-Salmon, C., ... 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