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Microtubule destabilization is shared by genetic and idiopathic Parkinson's disease patient fibroblasts.

ABSTRACT: Data from both toxin-based and gene-based models suggest that dysfunction of the microtubule system contributes to the pathogenesis of Parkinson's disease, even if, at present, no evidence of alterations of microtubules in vivo or in patients is available. Here we analyze cytoskeleton organization in primary fibroblasts deriving from patients with idiopathic or genetic Parkinson's disease, focusing on mutations in parkin and leucine-rich repeat kinase 2. Our analyses reveal that genetic and likely idiopathic pathology affects cytoskeletal organization and stability, without any activation of autophagy or apoptosis. All parkinsonian fibroblasts have a reduced microtubule mass, represented by a higher fraction of unpolymerized tubulin in respect to control cells, and display significant changes in microtubule stability-related signaling pathways. Furthermore, we show that the reduction of microtubule mass is so closely related to the alteration of cell morphology and behavior that both pharmacological treatment with microtubule-targeted drugs, and genetic approaches, by transfecting the wild type parkin or leucine-rich repeat kinase 2, restore the proper microtubule stability and are able to rescue cell architecture. Taken together, our results suggest that microtubule destabilization is a point of convergence of genetic and idiopathic forms of parkinsonism and highlight, for the first time, that microtubule dysfunction occurs in patients and not only in experimental models of Parkinson's disease. Therefore, these data contribute to the knowledge on molecular and cellular events underlying Parkinson's disease and, revealing that correction of microtubule defects restores control phenotype, may offer a new therapeutic target for the management of the disease.

SUBMITTER: Cartelli D

PROVIDER: S-EPMC3359730 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Microtubule destabilization is shared by genetic and idiopathic Parkinson's disease patient fibroblasts.

Cartelli Daniele D Goldwurm Stefano S Casagrande Francesca F Pezzoli Gianni G Cappelletti Graziella G

PloS one 20120522 5

Data from both toxin-based and gene-based models suggest that dysfunction of the microtubule system contributes to the pathogenesis of Parkinson's disease, even if, at present, no evidence of alterations of microtubules in vivo or in patients is available. Here we analyze cytoskeleton organization in primary fibroblasts deriving from patients with idiopathic or genetic Parkinson's disease, focusing on mutations in parkin and leucine-rich repeat kinase 2. Our analyses reveal that genetic and like ...[more]

PMID: 22666358

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Project description:Post-mortem Lewy body and Lewy neuritic inclusions are a defining feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). With the discovery of missense and multiplication mutations in the alpha-synuclein gene (SNCA) in familial parkinsonism, Lewy inclusions were found to stain intensely with antibodies raised against the protein. Yeast-two-hybrid studies identified synphilin-1 as an interacting partner of alpha-synuclein, and both proteins show co-immunolocalization in a subset of Lewy body inclusions. In the present study, we have investigated whether common variability in synphilin-1, including coding substitutions are genetically associated with disease pathogenesis.We screened the synphilin-1 gene for 11 single nucleotide polymorphisms (SNPs) in 300 affected subjects with idiopathic Parkinson's disease and 412 healthy controls. Six of these were rare variants including five previously identified amino acid substitutions that were chosen in a direct approach for association of rare disease causing mutations. An additional five highly heterozygous SNPs were chosen for an indirect association approach including haplotype analysis, based on the assumption that any disease causing mutations might be in linkage disequilibrium with the SNPs selected. We also genotyped a microsatellite marker (D5S2950) within intron 6 of the gene and five additional microsatellites clustered downstream of the 5p23.1-23.3 synphilin-1 locus. Genome-wide linkage analysis, in a number of independent studies, has previously highlighted suggestive linkage to PD in this region of chromosome 5.Screening of previously known amino acid substitutions in the synphilin-1 gene, identified the C1861>T (R621C) substitution in four patients (chromosomes n = 600) and 10 control subjects (chromosomes n = 824), whereas the G2125>C (E706Q) substitution was detected in one patient and four control subject, suggesting both these substitutions are not associated with susceptibility to PD. Heterozygous non-synonymous T131>C (V44A) and synonymous C636>T (P212P) amino acid substitutions were each detected in only one patient with PD. Heterozygous C1134>T (L378L) synonymous substitutions were found in two patients with PD and one control subject. D5S2010 the most distal telomeric microsatellite marker genotyped,15.3 Mb from synphilin-1, was genetically associated with PD (p = 0.006, 27df) independently adjusted for multiple testing according to its high amount of alleles but not the total number of other markers investigated. Other flanking and intronic SNP and microsatellite markers showed no evidence for genetic association with disease.In this study rare synphilin-1 SNPs were assessed in a direct association approach to identify amino acid substitutions that might confer risk of PD in a homozygous or compound heterozygous state. We found none of these rare variations were associated with disease. In contrast to prior studies the frequency of the R621C substitution was not significantly different between PD and control subjects, neither were the V44A or E706Q substitutions. Similarly, our indirect study of more heterozygous SNPs, including both single marker and haplotype analyses, showed no significant association to PD. However, marginal association of microsatellite alleles with idiopathic PD, within the chromosome 5q21 region, indicates further studies are warranted.

Project description:BackgroundEpidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.ObjectiveWe used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.MethodsWe used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses.ResultsWe confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31).ConclusionsWe show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Dataset Information

Microtubule destabilization is shared by genetic and idiopathic Parkinson's disease patient fibroblasts.

Publications

Microtubule destabilization is shared by genetic and idiopathic Parkinson's disease patient fibroblasts.

Similar Datasets

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