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15:58 EDT 25th June 2018 | BioPortfolio

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Showing "Lysosomal Storage Disorder Pipeline Review 2015" PubMed Articles 1–25 of 25,000+

Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.

Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. W...

The brain lipidome in neurodegenerative lysosomal storage disorders.

Cholesterol, sphingolipids and glycerophospholipids are critical constituents of the brain, subserving neuronal membrane architecture and providing a platform for biochemical processes essential for proper neurodevelopment and function. When lysosomal defects arise in a lipid metabolic pathway, it is therefore easy to imagine that neurological decline will transpire, however for deficits in non-lipid pathways, this becomes harder to envisage. Here we suggest the working hypothesis that neurodegenerative lys...

The intersection of lysosomal and endoplasmic reticulum calcium with autophagy defects in lysosomal diseases.

The lysosomal storage disorders (LSDs) encompass a group of more than 50 inherited diseases characterized by the accumulation of lysosomal substrates. Two-thirds of patients experience significant neurological symptoms, but the mechanisms of neurodegeneration are not well understood. Interestingly, a wide range of LSDs show defects in both autophagy and Ca homeostasis, which is notable as Ca is a key regulator of autophagy. The crosstalk between these pathways in the context of LSD pathogenesis is not well ...

Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency.

Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substr...

Is Parkinson's disease a lysosomal disorder?

Common forms of Parkinson's disease have long been described as idiopathic, with no single penetrant genetic factor capable of influencing disease aetiology. Recent genetic studies indicate a clear association of variants within several lysosomal genes as risk factors for idiopathic Parkinson's disease. The emergence of novel variants suggest that the aetiology of idiopathic Parkinson's disease may be explained by the interaction of several partially penetrant mutations that, while seemingly complex, all ap...

Defective collagen proteostasis and matrix formation in the pathogenesis of lysosomal storage disorders.

The lysosome is a catabolic organelle devoted to the degradation of cellular components, such as protein complexes and whole or portion of organelles that reach the lysosomes through (macro)autophagy. The lysosomes also function as signaling organelles by controlling the activity of key metabolic kinases, such as the mechanistic target of Rapamycin complex 1 (mTORC1). Lysosome dysfunction has dramatic consequences on cellular homeostasis and cause lysosomal storage disorders (LSDs). Here we review the recen...

Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation.

Defects in the MFSD8 gene encoding the lysosomal membrane protein CLN7 lead to CLN7 disease, a neurodegenerative lysosomal storage disorder belonging to the group of neuronal ceroid lipofuscinoses (NCLs). Here we have performed a SILAC-based quantitative analysis of the lysosomal proteome using Cln7-deficient mouse embryonic fibroblasts (MEFs) from a Cln7 knockout (ko) mouse model. From 3335 different proteins identified, we detected 56 soluble lysosomal proteins and 29 highly abundant lysosomal membrane pr...

Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones.

Misfolding of proteins is the basis of several proteinopathies. Chemical and pharmacological chaperones are small molecules capable of inducing the correct conformation of proteins, thus being of interest for human therapeutics. The most recent developments in medicinal chemistry and in the drug development of pharmacological chaperones are discussed, with focus on lysosomal storage diseases.

Screening Test of Fabry Disease in Patients with Renal Replacement Therapy in the City of Modena.

Fabry disease is a rare genetic lysosomal storage disease, inherited in an X-linked manner, characterized by lysosomal deposition of globotriaosylceramide due to deficient activity of the enzyme α-galactosidase A. Because the prevalence of this genetic disorder is unknown in the Emilia Romagna region, we conducted a screening study to assess the prevalence of Fabry disease in the city of Modena, Italy.

A ratiometric fluorescence probe for lysosomal polarity.

Lysosomal polarity affects the interaction activities between enzymes and substrates at the cellular level. Abnormal lysosomal polarity closely linked with disorders and diseases is worthy of attention. The first fluorescence probe, which can image polarity ratiometrically and detect lysosomal polarity quantitatively, is reported herein. The probe termed NOH can emit dual-peaks both in solvents (λ = 474, 552 nm) and in micro-environment. NOH exhibits the Boltzmann function response of the fluorescenc...

Widespread Vasculopathy in a Patient with Morquio A Syndrome.

Morquio A syndrome (mucopolysaccharidosis IV type A), an autosomal recessive lysosomal storage disorder caused by a defective N-acetylgalactosamine 6-sulfatase gene, leads to lysosomal accumulation of keratan sulfate and chondroitin 6-sulfate. This accumulation affects multiple systems and causes notable cardiovascular manifestations, such as thickening of the left-sided valves, ventricular hypertrophy, and intimal stenosis of the coronary arteries. There have been few reports of vasculopathy in this popula...

Pharmacotherapy of Gaucher Disease: Current and Future Options.

The clinical manifestations of Gaucher disease, a rare genetic lysosomal storage disorder, are debilitating, and the neuronopathic forms of the disease are fatal. The authors describe the current and investigational therapies for treatment.

Neonatal screening for four lysosomal storage diseases with a digital microfluidics platform: Initial results in Brazil.

We describe the initial results of a neonatal screening program for four lysosomal storage diseases (MPS I, Pompe, Gaucher and Fabry) using the digital microfluidics methodology. The method successfully identified patients previously diagnosed with these diseases and was used to test dried blood spot samples obtained from 10,527 newborns aged 2 to 14 days. The digital microfluidic technology shows potential for a simple, rapid and high-throughput screening for these four diseases in a standard neonatal scre...

Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies.

Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome. This review highlights the novel pathophysiological role of LAL, the functional genomic discoveries of LIPA as a risk locus for coronary heart diseases (CHD), and the clinical advance in therapies for LAL deficiency.

TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity.

TDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways. We observed that the lysosomal fusion ma...

The erythrocyte osmotic resistance test as screening tool for cholesterol-related lysosomal storage diseases.

Erythrocyte volume regulation and membrane elasticity are essential for adaptation to osmotic and mechanical stress, and life span. Here, we evaluated whether defective cholesterol trafficking caused by the rare lysosomal storages diseases (LSDs), Niemann-Pick type C (NPC) and Lysosomal acid lipase (LAL) deficiency (LALD) impairs these properties. Moreover, we tested whether measurements of cholesterol membrane content and osmotic resistance serve as a screening test for these LSDs.

Newborn Screening for Spinal Muscular Atrophy and Lysosomal Storage Disorders Takes Advantage of Novel Therapies.

Cardiac and renal dysfunction is associated with progressive hearing loss in patients with Fabry disease.

Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature.

Chaperone effect of sulfated disaccharide from heparin on mutant iduronate-2-sulfatase in mucopolysaccharidosis type II.

Small molecules called pharmacological chaperones have been shown to improve the stability, intracellular localization, and function of mutated enzymes in several lysosomal storage diseases, and proposed as promising therapeutic agents for them. However, a chaperone compound for mucopolysaccharidosis type II (MPS II), which is an X-linked lysosomal storage disorder characterized by a deficiency of iduronate-2-sulfatase (IDS) and the accumulation of glycosaminoglycans (GAGs), has still not been developed. He...

Partial loss of ATP13A2 causes selective gliosis independent of robust lipofuscinosis.

Loss-of-function mutations in ATP13A2 are associated with three neurodegenerative diseases: a rare form of Parkinson's disease termed Kufor-Rakeb syndrome (KRS), a lysosomal storage disorder termed neuronal ceroid lipofuscinosis (NCL), and a form of hereditary spastic paraplegia (HSP). Furthermore, recent data suggests that heterozygous carriers of mutations in ATP13A2 may confer risk for the development of Parkinson's disease, similar to the association of mutations in glucocerebrosidase (GBA) with both Pa...

Detection and Clearance of Damaged Lysosomes by the Endo-Lysosomal Damage Response and Lysophagy.

Lysosomal membrane permeabilization or lysosomal rupture is recognized as a common and severe stress condition relevant for infection, cellular degeneration and cancer. However, the cellular response mechanisms that protect cells from the consequences of lysosomal damage and ensure lysosomal quality control and homeostasis have only recently been explored. Key elements of this response involve the specific sensing of the damage followed by extensive modification of the organelles with ubiquitin to mark them...

Fluorescence-Quenched Substrates for Quantitative Live Cell Imaging of Glucocerebrosidase Activity.

Glucocerebrosidase (GCase) is a lysosomal glycoside hydrolase that cleaves the glycolipid glucosylceramide (GlcCer). Deficiencies of this enzyme lead to accumulation of GlcCer and the development of the lysosomal storage disease known as Gaucher's disease. Recently, loss-of-function mutations in the GBA1 gene that encodes GCase have been linked to Parkinson's disease. Currently pursued therapeutic strategies to increase GCase involve enzyme replacement therapy, chemical chaperone therapy, and GCase activato...

Systematic Review of Combined Pharmacotherapy for the Treatment of Alcohol Use Disorder in Patients Without Comorbid Conditions.

Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the strengths and limitations of current clinical evidence for the use of combined pharmacological interventions intended to treat alcohol use disorder.

Validation of a customized bioinformatics pipeline for a clinical next-generation sequencing test targeting solid tumor-associated variants.

Bioinformatic analysis is an integral and critical part of clinical next-generation sequencing. It is especially challenging for some pipelines to consistently identify insertions and deletions. We present the validation of an open source tumor amplicon pipeline (OTA-pipeline) for clinical next-generation sequencing targeting solid tumor-associated variants. Raw data generated from 557 TruSight Tumor 26 samples as well as in silico data were analyzed by the OTA-pipeline and legacy pipeline and compared. Dis...

The Interplay Between Apolipoprotein E4 and the Autophagic-Endocytic-Lysosomal Axis.

Since its discovery as a genetic risk factor for Alzheimer's disease, the APOE4 allele has been linked to the majority of the pathological findings associated with the disease progression. These include abnormalities of the endocytic, autophagic, and lysosomal machineries, which begin at the most early stages of Alzheimer's disease development. Considering that these three vesicular systems share common features and, in fact, comprise an interconnected cargo-trafficking and degradation network, some of the ...

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