Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify as a new gene implicated in PD and childhood neurodegeneration.
View Article and Find Full Text PDFBackground: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease.
View Article and Find Full Text PDFHealthcare (Basel)
February 2024
The prevalence of calcium deposits in coronary arteries grows with age. Risk factors include, e.g.
View Article and Find Full Text PDFBackground: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD.
View Article and Find Full Text PDFWe demonstrate that the Parkinson's VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding.
View Article and Find Full Text PDFPoint mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease and augment LRRK2's kinase activity. However, cellular pathways that endogenously enhance LRRK2 kinase function have not been identified. While overexpressed Rab29 draws LRRK2 to Golgi membranes to increase LRRK2 kinase activity, there is little evidence that endogenous Rab29 performs this function under physiological conditions.
View Article and Find Full Text PDFBackground: Stress hyperglycemia and lactates have been used separately as markers of a severe clinical condition and poor outcomes in patients with myocardial infarction (MI). However, the interplay between glucose and lactate metabolism in patients with MI have not been sufficiently studied. The aim in the present study was to examine the relationship of glycemia on admission (AG) and lactate levels and their impact on the outcome in non-diabetic MI patients treated with percutaneous coronary intervention (PCI).
View Article and Find Full Text PDFThe NEK1 kinase controls ciliogenesis, mitosis, and DNA repair, and mutations cause human diseases including axial spondylometaphyseal dysplasia and amyotrophic lateral sclerosis. mutations cause a similar pattern of human diseases, suggesting close functional links with Here, we report that endogenous NEK1 and C21ORF2 form a tight complex in human cells. A C21ORF2 interaction domain "CID" at the C-terminus of NEK1 is necessary for its association with C21ORF2 in cells, and pathogenic mutations in this region disrupt the complex.
View Article and Find Full Text PDFBackground: Atrial fibrillation (AF) is a common arrhythmia with increasing prevalence with respect to age and comorbidities. AF may influence the prognosis in patients hospitalized with Coronavirus disease 2019 (COVID-19). We aimed to assess the prevalence of AF among patients hospitalized due to COVID-19 and the association of AF and in-hospital anticoagulation treatment with prognosis.
View Article and Find Full Text PDFBackground: The impact of COVID-19 on the outcome of patients with MI has not been studied widely. We aimed to evaluate the relationship between concomitant COVID-19 and the clinical course of patients admitted due to acute myocardial infarction (MI).
Methods: There was a comparison of retrospective data between patients with MI who were qualified for coronary angiography with concomitant COVID-19 and control group of patients treated for MI in the preceding year before the onset of the pandemic.
Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease, and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al., 2017). Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation.
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April 2022
Auxetic structures exhibit unusual changes in size, expanding laterally upon stretching instead of contracting. This paper presents this effect in a failsafe mode in structures made of rigid squares. We applied the concept of auxetic structures made of rigid rotating squares (from Grima and Evans) and offer a novel solution for connecting them.
View Article and Find Full Text PDFPostepy Kardiol Interwencyjnej
December 2020
Introduction: Single-shot techniques such as cryoballoon and multipolar phased pulmonary vein ablation catheter (PVAC) are an alternative to the point-by-point radiofrequency method for atrial fibrillation (AF) ablation. However, there is a lack of data concerning sequential use of single-shot techniques, that is, for both the index and redo ablation.
Aim: To assess long-term outcomes of the 'single-shot techniques only' AF ablation strategy.
Autosomal dominant mutations in LRRK2 that enhance kinase activity cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases including Rab8A and Rab10 within its effector binding motif. Here, we explore whether LRRK1, a less studied homolog of LRRK2 that regulates growth factor receptor trafficking and osteoclast biology might also phosphorylate Rab proteins.
View Article and Find Full Text PDFMutations that increase the protein kinase activity of LRRK2 are one of the most common causes of familial Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif, impacting interaction with effectors. We describe and validate a new, multiplexed targeted mass spectrometry assay to quantify endogenous levels of LRRK2-phosphorylated Rab substrates (Rab1, Rab3, Rab8, Rab10, Rab35 and Rab43) as well as total levels of Rabs, LRRK2 and LRRK2-phosphorylated at the Ser910 and Ser935 biomarker sites.
View Article and Find Full Text PDFMutations that enhance LRRK2 protein kinase activity cause inherited Parkinson's disease. LRRK2 phosphorylates a group of Rab GTPase proteins, including Rab10 and Rab12, within the effector-binding switch-II motif. Previous work has indicated that the PARK16 locus, which harbors the gene encoding for Rab29, is involved in Parkinson's, and that Rab29 operates in a common pathway with LRRK2.
View Article and Find Full Text PDFMutations that activate LRRK2 protein kinase cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all human protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins.
View Article and Find Full Text PDFLRRK2 kinase mutations cause familial Parkinson's disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans-Golgi and activates it there, yet some of LRRK2's major Rab substrates are not on the Golgi. We sought to characterize the cell biology of LRRK2 activation.
View Article and Find Full Text PDFMissense mutations in the LRRK2 (Leucine-rich repeat protein kinase-2) and VPS35 genes result in autosomal dominant Parkinson's disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity.
View Article and Find Full Text PDFChlamydiae are frequently encountered Gram-negative intracellular eubacteria that can cause clear manifestations or clinically asymptomatic disorders. C. suis and other chlamydia are primarily isolated in cases of reproductive disorders.
View Article and Find Full Text PDFBackground: Mutations in LRRK2 are a common genetic cause of Parkinson's disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive.
View Article and Find Full Text PDFParkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector-binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with LRRK2. Here, we show that Rab29 recruits LRRK2 to the -Golgi network and greatly stimulates its kinase activity.
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