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

Abstract : BACKGROUND: Mutations of the gene encoding the major component of Lewy bodies (LB), alpha-synuclein (alpha-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 alpha-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 alpha-syn (hA30Palpha-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 alpha-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar alpha-syn species phosphorylated at S129 (PS129alpha-syn) were the predominant neuropathological feature in hA30Palpha-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and alpha-syn truncated at D135 (alpha-synD135), indicating that PS129alpha-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 alpha-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of alpha-syn deposits in end-stage disease.
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https://www.hal.inserm.fr/inserm-00903905
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Submitted on : Wednesday, November 13, 2013 - 12:49:26 PM
Last modification on : Wednesday, August 19, 2020 - 11:18:03 AM
Long-term archiving on: : Friday, February 14, 2014 - 8:15:29 AM

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Margot Fournier, Amandine Roux, Jérôme Garrigue, Marie-Paule Muriel, Paul Blanche, et al.. Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in alpha-synuclein transgenic mice.. BMC Neuroscience, BioMed Central, 2013, 14 (1), pp.135. ⟨10.1186/1471-2202-14-135⟩. ⟨inserm-00903905⟩

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