Abstract
BackgroundMutations 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.ResultsLongitudinal 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.ConclusionsThese 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.
Highlights
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
Most early-onset autosomal recessive cases of PD are due to mutations in the gene encoding Parkin [25,26], an E3 ubiquitin-protein ligase involved in the ubiquitylation of a number of substrates (e.g. CDCRel-1, Pael R, synphilin, p38/JTV1/AIMP2, Eps15) and in various cellular mechanisms, including signaling pathways, synaptic transmission, proteasomal protein degradation and the autophagy of dysfunctional mitochondria [25,27]
An antibody directed against α-syn truncated at D135 (α-synD135) was first incubated for 6 h in phosphate-buffered saline (PBS) supplemented with 4% bovine serum albumin (BSA), 10% newborn goat serum (NGS) with the recombinant proteins of interest (α-synD135, α-synY133 and α-syn), at an antibody:protein ratio of 1:2000
Summary
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. Most early-onset autosomal recessive cases of PD are due to mutations in the gene encoding Parkin [25,26], an E3 ubiquitin-protein ligase involved in the ubiquitylation of a number of substrates (e.g. CDCRel-1, Pael R, synphilin, p38/JTV1/AIMP2, Eps15) and in various cellular mechanisms, including signaling pathways, synaptic transmission, proteasomal protein degradation and the autophagy of dysfunctional mitochondria [25,27] It is unclear whether mutations in the α-syn and parkin genes converge into common neuropathological pathways. The overproduction of Parkin protects against α-syn-induced toxicity, both in vitro and in vivo [19,28,29,30], but conflicting results have been reported in models of Parkin depletion, which mimics the loss of protein function underlying PD due to parkin mutations [16,31] We explored this issue further, in mice producing the pathogenic human A30P variant of α-syn (hA30Pα-syn). We report that dysfunctional parkin alleles delay the onset of disease signs, in a dose-dependent manner, in hA30Pα-syn mice, with only modest effects on neuropathological characteristics in end-stage disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
