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

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

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 - BMC Neuroscience

JF - BMC Neuroscience

M1 - 135

ER -