Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mind the Gap: LRRK2 Phenotypes in the Clinic vs. in Patient Cells.

ABSTRACT: Mutations in the Parkinson's disease (PD) protein Leucine Rich Repeat Kinase 2 (LRRK2) have been under study for more than 15 years and our understanding of the cellular phenotypes for the pathogenic mutant forms of LRRK2 has significantly advanced. In parallel to research on LRRK2 mutations in experimental systems, clinical characterization of patients carrying LRRK2 mutations has advanced, as has the analysis of cells that are derived from these patients, including fibroblasts, blood-derived cells, or cells rendered pluripotent. Under the hypothesis that patient clinical phenotypes are a consequence of a cascade of underlying molecular mechanisms gone astray, we currently have a unique opportunity to compare findings from patients and patient-derived cells to ask the question of whether the clinical phenotype of LRRK2 Parkinson's disease and cellular phenotypes of LRRK2 patient-derived cells may be mutually informative. In this review, we aim to summarize the available information on phenotypes of LRRK2 mutations in the clinic, in patient-derived cells, and in experimental models in order to better understand the relationship between the three at the molecular and cellular levels and identify trends and gaps in correlating the data.

SUBMITTER: Goveas L

PROVIDER: S-EPMC8145309 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mind the replication gap.

Project description:Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved efficient pathways to restore stalled and/or collapsed replication forks during S-phase, and when necessary, also to delay cell cycle progression to ensure replication completion. However, strong evidence shows that cells can proceed to mitosis with incompletely replicated DNA when under mild replication stress (RS) conditions. Consequently, the incompletely replicated genomic gaps form, predominantly at common fragile site regions, where the converging fork-like DNA structures accumulate. These branched structures pose a severe threat to the faithful disjunction of chromosomes as they physically interlink the partially duplicated sister chromatids. In this review, we provide an overview discussing how cells respond and deal with the under-replicated DNA structures that escape from the S/G2 surveillance system. We also focus on recent research of a mitotic break-induced replication pathway (also known as mitotic DNA repair synthesis), which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions. Finally, we discuss recent data on how mild RS may cause chromosome instability and mutations that accelerate cancer genome evolution.

| S-EPMC8188003 | biostudies-literature

Patient satisfaction in shoulder arthroscopy: telemedicine vs. clinic follow-up visits.

Project description:BackgroundThe use of telemedicine for postoperative visits is increasing, especially in rural areas. Few studies have investigated its use for arthroscopic shoulder patients. This study aims to evaluate patient satisfaction with telemedicine for postoperative clinic visits following arthroscopic shoulder procedures in a rural setting.MethodsPatients were prospectively enrolled using the following exclusion criteria: <18 years, open procedures, and non-compliance follow-up at 6 weeks postoperatively. All patients completed a 13-question satisfaction survey, while telemedicine patients completed an additional, separate seven-question survey. Patients who switched groups completed a four-question prompt to determine the reasons for switching. Differences between groups were evaluated by either Student t-test or Mann-Whitney U-test.ResultsThe study enrolled 32 patients, with five patients following up by telemedicine and 27 in person. Age and distance from clinic were similar between patients who were assigned to the telemedicine group, completed the telemedicine visit, and opted for in-person visits (all p>0.05). Patient satisfaction did not vary significantly based on care by the surgeon, concerns being addressed, thoroughness of visit, overall clinical assessment at a prior visit, and improvements in pain and physical function (all p>0.05). Among patients who opted out of telemedicine visits, the most common reason was a preference to meet in-person but these patients agreed that telemedicine visits are a good idea.ConclusionsRegardless of type of follow-up, individuals reported similar levels of satisfaction with treatment during the visit and improvements in pain and physical function.

| S-EPMC9185120 | biostudies-literature

Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers.

Project description:ObjectiveTo test whether phosphorylated Ser-1292 LRRK2 levels in urine exosomes predicts LRRK2 mutation carriers (LRRK2+) and noncarriers (LRRK2-) with Parkinson disease (PD+) and without Parkinson disease (PD-).MethodsLRRK2 protein was purified from urinary exosomes collected from participants in 2 independent cohorts. The first cohort included 14 men (LRRK2+/PD+, n = 7; LRRK2-/PD+, n = 4; LRRK2-/PD-, n = 3). The second cohort included 62 men (LRRK2-/PD-, n = 16; LRRK2+/PD-, n = 16; LRRK2+/PD+, n = 14; LRRK2-/PD+, n = 16). The ratio of Ser(P)-1292 LRRK2 to total LRRK2 was compared between LRRK2+/PD+ and LRRK2- in the first cohort and between LRRK2 G2019S carriers with and without PD in the second cohort.ResultsLRRK2+/PD+ had higher ratios of Ser(P)-1292 LRRK2 to total LRRK2 than LRRK2-/PD- (4.8-fold, p < 0.001) and LRRK2-/PD+ (4.6-fold, p < 0.001). Among mutation carriers, those with PD had higher Ser(P)-1292 LRRK2 to total LRRK2 than those without PD (2.2-fold, p < 0.001). Ser(P)-1292 LRRK2 levels predicted symptomatic from asymptomatic carriers with an area under the receiver operating characteristic curve of 0.844.ConclusionElevated ratio of phosphorylated Ser-1292 LRRK2 to total LRRK2 in urine exosomes predicted LRRK2 mutation status and PD risk among LRRK2 mutation carriers. Future studies may explore whether interventions that reduce this ratio may also reduce PD risk.

| S-EPMC4799717 | biostudies-literature

Pulmonary mucormycosis in the aftermath of critical COVID-19 in an immunocompromised patient: Mind the diagnostic gap.

Project description:Mucormycosis has recently been recognized as a severe complication of COVID-19 with high fatality rates. We report a fatal case of COVID-19 associated mucormycosis (CAM) in a non-diabetic immunocompromised patient, who was first misdiagnosed and treated for COVID-19 associated aspergillosis (CAPA). The risk factors and initial clinical presentation of CAPA and CAM are similar, but CAM has a more aggressive course and CAPA and CAM are treated differently. Dedicated diagnostic workup is essential to ensure early treatment of CAM with surgical debridement and targeted antifungal therapy.

| S-EPMC8600800 | biostudies-literature

Global disparities in arrhythmia care: Mind the gap.

Project description:Delivery of comprehensive arrhythmia care requires the simultaneous presence of many resources. These include complex hospital infrastructure, expensive implantable equipment, and expert personnel. In many low- and middle-income countries (LMICs), at least 1 of these components is often missing, resulting in a gap between the demand for arrhythmia care and the capacity to supply care. In addition to this treatment gap, there exists a training gap, as many clinicians in LMICs have limited access to formal training in cardiac electrophysiology. Given the progressive increase in the burden of cardiovascular diseases in LMICs, these patient care and clinical training gaps will widen unless further actions are taken to build capacity. Several strategies for building arrhythmia care capacity in LMICs have been described. Medical missions can provide donations of both equipment and clinical expertise but are only intermittently present and therefore are not optimized to provide the longitudinal support needed to create self-sustaining infrastructure. Use of donated or reprocessed equipment (eg, cardiac implantable electronic devices) can reduce procedural costs but does not address the need for infrastructure, including diagnostics and expert personnel. Collaborative efforts involving multiple stakeholders (eg, professional organizations, government agencies, hospitals, and educational institutions) have the potential to provide longitudinal support of both patient care and clinician education in LMICs.

| S-EPMC9795303 | biostudies-literature

Identification of Targets from LRRK2 Rescue Phenotypes.

Project description:Parkinson's disease (PD) is an age-dependent neurodegenerative condition. Leucine-rich repeat kinase 2 (LRRK2) mutations are the most frequent cause of sporadic and autosomal dominant PD. The exact role of LRRK2 protective variants (R1398H, N551K) together with a pathogenic mutant (G2019S) in aging and neurodegeneration is unknown. We generated the following myc-tagged UAS-LRRK2 transgenic Drosophila: LRRK2 (WT), N551K, R1398H, G2019S single allele, and double-mutants (N551K/G2019S or R1398H/G2019S). The protective variants alone were able to suppress the phenotypic effects caused by the pathogenic LRRK2 mutation. Next, we conducted RNA-sequencing using mRNA isolated from dopaminergic neurons of these different groups of transgenic Drosophila. Using pathway enrichment analysis, we identified the top 10 modules (p < 0.05), with "LRRK2 in neurons in Parkinson's disease" among the candidates. Further dissection of this pathway identified the most significantly modulated gene nodes such as eEF1A2, ACTB, eEF1A, and actin cytoskeleton reorganization. The induction of the pathway was successfully restored by the R1398H protective variant and R1398H-G2019S or N551K-G2019S rescue experiments. The oxidoreductase family of genes was also active in the pathogenic mutant and restored in protective and rescue variants. In summary, we provide in vivo evidence supporting the neuroprotective effects of LRRK2 variants. RNA sequencing of dopaminergic neurons identified upregulation of specific gene pathways in the Drosophila carrying the pathogenic variant, and this was restored in the rescue phenotypes. Using protective gene variants, our study identifies potential new targets and provides proof of principle of a new therapeutic approach that will further our understanding of aging and neurodegeneration in PD.

| S-EPMC7824855 | biostudies-literature

GAP aflR- vs WT timecourse

Project description:The carcinogen aflatoxin is synthesized by a cluster of genes that are regulated by the transcriptional factor, AflR. Most, but not all of these genes, have a consensus binding site for AflR in their 5’ untranslated region. Because aflR resides within the biosynthetic cluster, is has been suggested that it regulates only genes within the cluster. The objective of this study was to identify those genes transcriptionally regulated by AflR and to determine if any of those genes reside outside the aflatoxin biosynthetic cluster. To address this objective, we employed a cDNA microarray of 5,002 genes from Aspergillus flavus to monitor the expression of genes in a wild type and an aflR deletion strain of A. parasiticus. Keywords = aspergillus Keywords = aflatoxin Keywords = regulation Keywords = secondary metabolism Keywords: time-course

2006-06-01 | GSE2709 | GEO

Bacterial Proliferation: Keep Dividing and Don't Mind the Gap.

Project description:DNA Damage Tolerance (DDT) mechanisms help dealing with unrepaired DNA lesions that block replication and challenge genome integrity. Previous in vitro studies showed that the bacterial replicase is able to re-prime downstream of a DNA lesion, leaving behind a single-stranded DNA gap. The question remains of what happens to this gap in vivo. Following the insertion of a single lesion in the chromosome of a living cell, we showed that this gap is mostly filled in by Homology Directed Gap Repair in a RecA dependent manner. When cells fail to repair this gap, or when homologous recombination is impaired, cells are still able to divide, leading to the loss of the damaged chromatid, suggesting that bacteria lack a stringent cell division checkpoint mechanism. Hence, at the expense of losing one chromatid, cell survival and proliferation are ensured.

| S-EPMC4699847 | biostudies-literature

Etiology of esophageal atresia and tracheoesophageal fistula: "mind the gap".

Project description:Esophageal atresia and tracheoesophageal fistula (EA/TEF) are major congenital malformations affecting 1:3500 live births. Current research efforts are focused on understanding the etiology of these defects. We describe well-known animal models, human syndromes, and associations involving EA/TEF, indicating its etiologically heterogeneous nature. Recent advances in genotyping technology and in knowledge of human genetic variation will improve clinical counseling on etiologic factors. This review provides a clinical summary of environmental and genetic factors involved in EA/TEF.

| S-EPMC2874026 | biostudies-literature

Socioeconomic gradient in health: mind the gap in 'invisible' disparities.

Project description: Not available

| S-EPMC7576022 | biostudies-literature