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

doi:10.1186/1471-2202-14-135

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^*

^*Corresponding author for this work

Section of Biostatistics

5 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 (P^S129α-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 P^S129α-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 language	English
Article number	135
Journal	BMC Neuroscience
Volume	14
ISSN	1471-2202
DOIs	https://doi.org/10.1186/1471-2202-14-135
Publication status	Published - 5 Nov 2013

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Fournier, M., Roux, A., Garrigue, J., Muriel, M. P., Blanche, P., Lashuel, H. A., Anderson, J. P., Barbour, R., Huang, J., du Montcel, S. T., Brice, A., & Corti, O. (2013). Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice. BMC Neuroscience, 14, [135]. https://doi.org/10.1186/1471-2202-14-135

@article{e97250c9d17e4076b8f75e741b029579,

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 = nov,

day = "5",

doi = "10.1186/1471-2202-14-135",

language = "English",

volume = "14",

journal = "B M C Neuroscience",

issn = "1471-2202",

publisher = "BioMed Central Ltd.",

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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

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U2 - 10.1186/1471-2202-14-135

DO - 10.1186/1471-2202-14-135

M3 - Journal article

C2 - 24192137

AN - SCOPUS:84887033337

SN - 1471-2202

VL - 14

JO - B M C Neuroscience

JF - B M C Neuroscience

M1 - 135

ER -

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

Abstract

Keywords

UN SDGs

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