Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease? DOI Open Access

Zuzanna Cyske,

Lidia Gaffke, Karolina Pierzynowska

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9570 - 9570

Published: Sept. 4, 2024

Several years ago, dozens of cases were described in patients with symptoms very similar to mucopolysaccharidosis (MPS). This new disease entity was as mucopolysaccharidosis-plus syndrome (MPSPS). The name the indicates that addition typical conventional MPS, develop other features such congenital heart defects and kidney hematopoietic system disorders. are highly advanced, usually do not survive past second year life. MPSPS is inherited an autosomal recessive manner caused by a homozygous-specific mutation gene encoding VPS33A protein. To date, it has been 41 patients. Patients exhibited excessive excretion glycosaminoglycans (GAGs) urine exceptionally high levels heparan sulfate plasma, but accumulation substrates decrease activity any lysosomal enzymes. Here, we discuss pathomechanisms MPSPS, comparing them those MPS. Moreover, asked question whether should be classified type MPS or separate disease, contrary ‘classical’ types, despite GAG accumulation, no enzymes responsible for degradation these compounds could detected MPSPS. molecular mechanism appearance suggested on basis results available literature.

Language: Английский

HOPS, CORVET and newly-identified Hybrid tethering complexes contribute differentially towards multiple modes of endocytosis DOI Creative Commons
Seigo Terawaki,

Filipp Vasilev,

Takahito Moriwaki

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 31, 2023

Abstract Vesicular transport driven by membrane trafficking systems conserved in eukaryotes is critical to cellular functionality and homeostasis. It known that homotypic fusion vacuole protein sorting (HOPS) class C core endosomal tethering (CORVET) interact with Rab-GTPases SNARE proteins regulate vesicle transport, fusion, maturation autophagy endocytosis pathways. In this study, we identified two novel “Hybrid” complexes mammalian cells which one of the subunits HOPS or CORVET replaced subunit from other. Substrates taken up receptor-mediated pinocytosis were transported distinctive pathways, newly hybrid contributed presence HOPS, whereas was exclusively dependent on HOPS. Our study provides new insights into molecular mechanisms endocytic pathway function vacuolar sorting-associated (VPS) family.

Language: Английский

Citations

9
Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat DOI Open Access
Bruno Hay Mele, Federica Rossetti, Maria Vittoria Cubellis

et al.

Genes, Journal Year: 2024, Volume and Issue: 15(3), P. 290 - 290

Published: Feb. 25, 2024

Rare diseases, or orphan are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), cluster rare metabolic characterized by enzyme mutations causing abnormal glycolipid storage. Drug repositioning involves repurposing existing approved drugs for new therapeutic applications, offering advantages in cost, time savings, and lower risk failure. We present comprehensive analysis drugs, their potential, clinical implications context LSDs, highlighting necessity mutation-specific approaches. Our review systematically explores landscape drug means enhance LSDs therapies. The findings advocate strategic accentuating its role expediting discovery effective treatments. conclude that represents viable pathway accelerating emphasizing need careful evaluation efficacy toxicity disease-specific contexts.

Language: Английский

Citations

2
An update on autophagy disorders DOI Creative Commons
Hormos Salimi Dafsari, Diego Martinelli, Afshin Saffari

et al.

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 17, 2024

Abstract Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, macromolecular complexes. As autophagy particularly relevant homeostasis in post‐mitotic tissues, congenital disorders autophagy, due to monogenic defects key genes, share common “clinical signature” neurodevelopmental, neurodegenerative, neuromuscular features, as well variable abnormalities eyes, skin, heart, bones, immune cells, other organ systems, depending on expression pattern specific function proteins. Since clinical genetic resolution EPG5 ‐related Vici syndrome, paradigmatic disorder widespread use massively parallel sequencing has resulted identification growing number autophagy‐associated disease encoding members core machinery related Recently identified linking selective vesicular trafficking, pathways have further expanded molecular phenotypical spectrum spectrum. Moreover, significant advances basic research enhanced understanding underlying pathophysiology basis therapy development. Here, we review (i) context intracellular trafficking pathways; (ii) main their typical clinico‐pathological signatures; (iii) recommended primary health surveillance based available evidence. We discuss recently mechanisms that inform current disease, perspectives future therapeutic approaches.

Language: Английский

Citations

2
Contribution of vesicle trafficking dysregulation to the pathomechanism of mucopolysaccharidosis DOI Creative Commons
Lidia Gaffke, Karolina Pierzynowska,

Zuzanna Cyske

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2023, Volume and Issue: 665, P. 107 - 117

Published: April 30, 2023

Although mucopolysaccharidoses (MPS) are monogenic diseases, caused by mutations in genes coding for enzymes involved degradation of glycosaminoglycans (GAGs), recent studies suggested that changes expressions various might cause secondary and tertiary cellular dysfunctions modulating the course these diseases. In this report, we demonstrate vesicle trafficking regulation is affected fibroblasts derived from patients suffering 11 different types MPS due to levels crucial proteins (estimated automated Western-blotting) process, including caveolin, clathrin, huntingtin (Htt), APPL1, EEA1, GOPC, Rab5, Rab7. Microscopic confirmed results, while investigations tissue samples I mouse model indicated differences between organs matter. Moreover, transcriptomic analyses provided a global picture related cells. We conclude dysregulated cells process contribute molecular mechanisms disease. Most probably, primary GAG storage stress response leading dysregulation expression many which, turn, results processes like trafficking. This can significantly modulate disease enhancing accumulation GAGs altering processes. hypothesis has been supported normalization clathrin treated with either an active form deficient GAG-degrading enzyme or compound (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) indirectly reducing efficiency synthesis.

Language: Английский

Citations

6
Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A DOI Open Access
Elena Pavlova, Dorit Lev, Marina Michelson

et al.

Human Mutation, Journal Year: 2022, Volume and Issue: 43(12), P. 2265 - 2278

Published: Sept. 25, 2022

A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components the membrane-tethering protein complexes, HOPS, CORVET. Whole exome sequencing identified a novel VPS33A mutation patient suffering from variant form mucopolysaccharidosis. Electron confocal microscopy, immunoblotting, glycosphingolipid experiments were undertaken investigate effects mutant patient-derived skin fibroblasts. We describe an attenuated juvenile VPS33A-related syndrome-mucopolysaccharidosis plus man who homozygous for hitherto unknown missense (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) conserved region gene. Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates, hyaluronic acid. showed decreased abundance derived fibroblasts provided evidence that p.Arg200Pro leads destablization proteasomal degradation. As infantile plus, compartment also expanded-a phenomenon accompanied endolysosomal acidification trafficking. Experimental treatment patient's cultured with proteasome inhibitor, bortezomib, or exposure inhibitor glucosylceramide synthesis, eliglustat, improved To our knowledge this first report insufficiency characterized appreciable residual endosomal-lysosomal milder than infants. Our findings expand proof concept redeploying clinically approved drugs therapeutic exploitation patients as well forms disease.

Language: Английский

Citations

7
Prenatal Diagnosis of Mucopolysaccharidosis-Plus Syndrome (MPSPS) DOI Open Access
Viktoriia Sofronova,

L. Gotovtseva,

Anastasia Danilova

et al.

Genes, Journal Year: 2023, Volume and Issue: 14(8), P. 1581 - 1581

Published: Aug. 3, 2023

Mucopolysaccharidosis-plus syndrome (MPSPS) is an autosomal-recessive disorder caused by c.1492C>T (p.R498W) in the VPS33A gene. MPSPS a severe that causes short lifespan patients. Currently, there no specific treatment for The Yakut population more prone to this disease than others. Diagnosing relies on clinical manifestations, and genetic testing (GT) used confirm diagnosis. In research, we examined two pregnancy cases, one of which involved prenatal diagnosis MPSPS. Notably, neither pregnant woman had known family history disorder. During their pregnancies, both women underwent ultrasonography, revealed increased prenasal thickness during second trimester. first case, ultrasonography indicated trimester, but definitive was not made at time. patient eventually diagnosed with 11 months age. On contrary, GT uncovered parents were carriers Consequently, placental biopsy performed, leading early This study emphasizes importance findings Combining can be valuable approach confirming stage, allowing appropriate planning delivery methods medical care. Ultimately, comprehensive significantly enhance quality life affected patients parents.

Language: Английский

Citations

4
Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease? DOI Open Access

Zuzanna Cyske,

Lidia Gaffke, Karolina Pierzynowska

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9570 - 9570

Published: Sept. 4, 2024

Several years ago, dozens of cases were described in patients with symptoms very similar to mucopolysaccharidosis (MPS). This new disease entity was as mucopolysaccharidosis-plus syndrome (MPSPS). The name the indicates that addition typical conventional MPS, develop other features such congenital heart defects and kidney hematopoietic system disorders. are highly advanced, usually do not survive past second year life. MPSPS is inherited an autosomal recessive manner caused by a homozygous-specific mutation gene encoding VPS33A protein. To date, it has been 41 patients. Patients exhibited excessive excretion glycosaminoglycans (GAGs) urine exceptionally high levels heparan sulfate plasma, but accumulation substrates decrease activity any lysosomal enzymes. Here, we discuss pathomechanisms MPSPS, comparing them those MPS. Moreover, asked question whether should be classified type MPS or separate disease, contrary ‘classical’ types, despite GAG accumulation, no enzymes responsible for degradation these compounds could detected MPSPS. molecular mechanism appearance suggested on basis results available literature.

Language: Английский

Citations

1