Pregnancy in Parkinson's disease with PARK2 mutations.
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ABSTRACT:
SUBMITTER: Sazci A
PROVIDER: S-EPMC8288558 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2-q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2-q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.
| S-EPMC4002225 | biostudies-literature
Project description:Parkinson's disease (PD) is a neurodegenerative pathology caused by progressive loss of dopaminergic neurons in the substantia nigra. Juvenile PD is known to be strongly associated with mutations in the PARK2 gene encoding E3 ubiquitin ligase Parkin. Despite numerous studies, molecular mechanisms that trigger PD still remain unknown. Here, we presented the transcriptome profile for neural progenitors (NP) which were obtained from iPSCs of Parkinson's disease patient, transduced with lentiviral particles carrying the full-length copy of cDNA PARK2. Transcriptome profiles were generated on an NextSeq 500 System (Illumina). A comparative transcriptome analysis of this data along with transcriptome profiles for NP of healthy donors and other patients with PD will allow determining the contribution of mutations of the PARK2 gene to PD pathogenesis and identifying genes whose expression depends on PARK2 overexpression.
2022-06-03 | GSE205235 | GEO
Project description:A new pathomechanism of Parkinson's disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability.104 early-onset PD patients (EOPD, age at onset ? 50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay.PARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C > A, P333P). In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p = 0.040; p = 0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04-4.04; p = 0.038).Our results indicate that co-occurrence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients.
| S-EPMC3358581 | biostudies-literature
Project description:Parkinson's disease (PD) is a common neurodegenerative disorder affecting mostly elderly people, although there is a group of patients developing so-called early-onset PD (EOPD). Mutations in the PARK2 gene are a common cause of autosomal recessive EOPD. PARK2 belongs to the family of extremely large human genes which are often localised in genomic common fragile sites (CFSs) and exhibit gross instability. PARK2 is located in the centre of FRA6E, the third most mutation-susceptible CFS of the human genome. The gene encompasses a region of 1.3 Mbp and, among its mutations, large rearrangements of single or multiple exons account for around 50%. We performed an analysis of the PARK2 gene in a group of 344 PD patients with EOPD and classical form of the disease. Copy number changes were first identified using multiplex ligation probe amplification (MLPA), with their ranges characterised by array comparative genomic hybridisation (aCGH). Exact breakpoints were mapped using direct sequencing. Rearrangements were found in eight subjects, including five deletions and three duplications. Rearrangements were mostly non-recurrent and no repetitive sequences or extended homologies were identified in the regions flanking breakpoint junctions. However, in most cases, 1-3 bp microhomologies were present, strongly suggesting that microhomology-mediated mechanisms, specifically non-homologous end joining (NHEJ) and fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR), are predominantly involved in the rearrangement processes in this genomic region.
| S-EPMC4617850 | biostudies-literature
Project description:ObjectiveTo investigate the oxidized albumin ratio, which is the redox ratio of human nonmercaptalbumin (HNA) to serum albumin (%HNA), as a biomarker in idiopathic Parkinson's disease (iPD) and related neurodegenerative disorders.MethodsThis prospective study enrolled 216 iPD patients, 15 patients with autosomal recessive familial PD due to parkin mutations (PARK2), 30 multiple system atrophy (MSA) patients, 32 progressive nuclear palsy (PSP) patients, and 143 healthy controls. HNA was analyzed using modified high-performance liquid chromatography and was evaluated alongside other parameters.ResultsiPD and PARK2 patients had a higher %HNA than controls (iPD vs. controls: odds ratio (OR) 1.325, P < 0.001; PARK2 vs. controls: OR 1.712, P < 0.001). Even iPD patients at an early Hoehn & Yahr stage (I and II) showed a higher %HNA than controls. iPD patients had a higher %HNA than MSA and PSP patients (iPD vs. MSA: OR 1.249, P < 0.001, iPD vs. PSP: OR 1.288, P < 0.05). When discriminating iPD patients from controls, %HNA corrected by age achieved an AUC of 0.750; when discriminating iPD patients from MSA and PSP patients, an AUC of 0.747 was achieved. Furthermore, uric acid, an antioxidant compound, was decreased in iPD patients, similar to the change in %HNA.Interpretation%HNA was significantly increased in iPD and PARK2 patients compared with controls, regardless of disease course and severity. Oxidative stress might be increased from the early stages of iPD and PARK2 and play an important role in their pathomechanisms.
| S-EPMC7086006 | biostudies-literature
Project description:ObjectsTo capture point mutations and short insertions/deletions in 49 previously reported genes associated with Parkinson's disease (PD) in a Chinese pedigree with early-onset Parkinson's disease (EOPD)-affected individuals.MethodsClinical examinations and genomic analysis were performed on 21 subjects belonging to three generations of a Chinese family. Target region capture and high-throughput sequencing were used for screening 49 genes, which were previously reported to be associated with PD. The direct Sanger sequencing method in all subjects further verified the abnormal DNA fragments in the PARK2 gene.ResultsFour family members, including a mother (I-1) and her three children (II-2, II-3, and II-7), were diagnosed with PD by clinical manifestations and/or PET/CT imaging analyses. Novel compound heterozygous mutations, consisting of a fragment deletion in exon 1 to 2 (EX 1-2 del) and a splicing point mutation c.619-1 (G > C) in the 6th intron of the PARK2 gene, were identified in II-2, II-3, and II-7. Individual EX 1-2 del or c.619-1 (G > C) mutations were detected in I-1 and the third generation (III-2, 3, 5, 10, and 11).Other mutations were not detected in the 49 known PD-associated genes.ConclusionNovel compound heterozygous mutations were identified in a Chinese pedigree and might represent a cause of familial EOPD with autosomal dominant inheritance.
| S-EPMC5853629 | biostudies-literature
Project description:Parkinson's disease (PD) is a complex systemic disease caused by neurodegenerative processes in the brain, in which the death of dopaminergic neurons (DN) of the substantia nigra is primarily noted. 50% of cases of familial PD are associated with mutations in the PARK2 gene. Induced pluripotent stem cells (iPSCs) and their neuronal derivatives are powerful tool for disease modeling. Here, we presented the transcriptome profiles for neural progenitors (NP) and neurons, presumably DN, differentiated from iPSC lines of healthy donors and PARK2 mutations-associated PD patients generated on an NextSeq 500 System (Illumina). A comparative transcriptome analysis of neuronal derivatives of healthy donors and patients with PD will allow determining the contribution of mutations of the PARK2 gene to PD pathogenesis upon neuronal differentiation.
2021-08-19 | GSE181029 | GEO
Project description:We report generation of induced pluripotent stem cell (iPSC) lines from ten Parkinson's disease (PD) patients carrying SNCA, PARK2, LRRK2, and GBA mutations, and one age-matched control. After validation of pluripotency, long-term genome stability, and integration-free reprogramming, eight of these lines (one of each SNCA, LRRK2 and GBA, four PARK2 lines, and the control) were differentiated into neural stem cells (NSC) and subsequently to dopaminergic cultures. We did not observe significant differences in the timeline of neural induction and NSC derivation between the patient and control line, nor amongst the patient lines, although we report considerable variability in the efficiency of dopaminergic differentiation among patient lines. We performed whole genome expression analyses of the lines at each stage of differentiation (fibroblast, iPSC, NSC, and dopaminergic culture) in an attempt to identify alterations by large-scale evaluation. While gene expression profiling clearly distinguished cells at different stages of differentiation, no mutation-specific clustering or difference was observed, though consistent changes in patient lines were detected in genes associated mitochondrial biology. We further examined gene expression in a stress model (MPTP-induced dopaminergic neuronal death) using two clones from the SNCA triplication line, and detected changes in genes associated with mitophagy. Our data suggested that even a well-characterized line of a monogenic disease may not be sufficient to determine the cause or mechanism of the disease, and highlights the need to use more focused strategies for large-scale data analysis.
| S-EPMC4871453 | biostudies-literature
Project description:Mutations of the TARDBP gene encoding TDP-43 protein have been shown to cause amyotrophic lateral sclerosis and have been reported to present with clinical heterogeneity including parkinsonism. In addition, TDP-43 pathology has been observed across a spectrum of neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Herein we report the presence of a TDP-43 mutation in a patient with a clinical diagnosis of Parkinson's disease. The TDP-43 p.N267S substitution has been previously implicated in both amyotrophic lateral sclerosis and behavioral variant frontotemporal dementia. Our findings widen the phenotypic presentation for the TDP-43 p.N267S substitution and support a possible role for rare TDP-43 mutations presenting with Parkinson's disease.
| S-EPMC3582838 | biostudies-literature
Project description:BACKGROUND AND PURPOSE:There is some controversy regarding heterozygous mutations of the gene encoding parkin (PARK2) as risk factors for Parkinson's disease (PD), and all previous studies have been performed in non-Asian populations. Dosage mutation of PARK2, rather than a point mutation or small insertion/deletion mutation, was reported to be a risk factor for familial PD; dosage mutation of PARK2 is common in Asian populations. METHODS:We performed a gene-dosage analysis of PARK2 using real-time polymerase chain reaction for 189 patients with early-onset PD or familial PD, and 191 control individuals. In the case of PD patients with heterozygous gene-dosage mutation, we performed a sequencing analysis to exclude compound heterozygous mutations. The association between heterozygous mutation of PARK2 and PD was tested. RESULTS:We identified 22 PD patients with PARK2 mutations (11.6%). Five patients (2.6%) had compound heterozygous mutations, and 13 patients (6.9%) had a heterozygous mutation. The phase could not be determined in one patient. Three small sequence variations were found in 30 mutated alleles (10.0%). Gene-dosage mutation accounted for 90% of all of the mutations found. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD patients than in the controls. CONCLUSIONS:Heterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.
| S-EPMC4101102 | biostudies-literature