المؤلفون: Lipiński, Patryk¹ (AUTHOR) patryk.lipinski.92@gmail.com, Tylki-Szymańska, Anna² (AUTHOR) a.tylki@ipczd.pl

المصدر: Diagnostics (2075-4418). Jun2024, Vol. 14 Issue 12, p1299. 11p.

مصطلحات موضوعية: *LYSOSOMAL storage diseases, *SYMPTOMS, *GLYCOGEN storage disease type II, *NIEMANN-Pick diseases, *GAUCHER'S disease, *LIVER

مستخلص: The liver, given its role as the central metabolic organ, is involved in many inherited metabolic disorders, including lysosomal storage diseases (LSDs). The aim of this manuscript was to provide a comprehensive overview on liver involvement in LSDs, focusing on clinical manifestation and its pathomechanisms. Gaucher disease, acid sphingomyelinase deficiency, and lysosomal acid lipase deficiency were thoroughly reviewed, with hepatic manifestation being a dominant clinical phenotype. The natural history of liver disease in the above-mentioned lysosomal disorders was delineated. The importance of Niemann–Pick type C disease as a cause of cholestatic jaundice, preceding neurological manifestation, was also highlighted. Diagnostic methods and current therapeutic management of LSDs were also discussed in the context of liver involvement. [ABSTRACT FROM AUTHOR]

المؤلفون: Xia, Jianhong¹ (AUTHOR) jhxia2006@163.com, Wang, Haiyun^1,2 (AUTHOR) sunny.haiyun@gmail.com, Zhong, Zhihang^3,4 (AUTHOR) zhongzhihanggood@163.com, Jiang, Jun^3,4 (AUTHOR) jiangjun@scau.edu.cn

المصدر: Cells (2073-4409). Jun2024, Vol. 13 Issue 11, p953. 18p.

مصطلحات موضوعية: *LYSOSOMAL storage diseases, *MTOR inhibitors, *CELL culture, *BRACHYDANIO, *HOMEOSTASIS

مستخلص: PIKfyve is an endosomal lipid kinase that synthesizes phosphatidylinositol 3,5-biphosphate from phosphatidylinositol 3-phsphate. Inhibition of PIKfyve activity leads to lysosomal enlargement and cytoplasmic vacuolation, attributed to impaired lysosomal fission processes and homeostasis. However, the precise molecular mechanisms underlying these effects remain a topic of debate. In this study, we present findings from PIKfyve-deficient zebrafish embryos, revealing enlarged macrophages with giant vacuoles reminiscent of lysosomal storage disorders. Treatment with mTOR inhibitors or effective knockout of mTOR partially reverses these abnormalities and extend the lifespan of mutant larvae. Further in vivo and in vitro mechanistic investigations provide evidence that PIKfyve activity is essential for mTOR shutdown during early zebrafish development and in cells cultured under serum-deprived conditions. These findings underscore the critical role of PIKfyve activity in regulating mTOR signaling and suggest potential therapeutic applications of PIKfyve inhibitors for the treatment of lysosomal storage disorders. [ABSTRACT FROM AUTHOR]

المؤلفون: Kuznetsov, Alexander¹ (AUTHOR), Sheshil, Andrey¹ (AUTHOR), Smolin, Eugene¹ (AUTHOR), Grudtsov, Vitaliy¹ (AUTHOR), Ryazantsev, Dmitriy¹ (AUTHOR), Shustinskiy, Mark¹ (AUTHOR), Tikhonova, Tatiana¹ (AUTHOR), Kitiashvili, Irakli² (AUTHOR), Vechorko, Valerii² (AUTHOR), Komarova, Natalia¹ (AUTHOR) nat.v.kom@gmail.com

المصدر: Sensors (14248220). Jun2024, Vol. 24 Issue 11, p3681. 12p.

مصطلحات موضوعية: *FIELD-effect transistors, *LYSOSOMAL storage diseases, *ANGIOKERATOMA corporis diffusum, *ENZYME replacement therapy, *NEWBORN screening, *COMPLEMENTARY metal oxide semiconductors

مستخلص: Fabry disease is a lysosomal storage disorder caused by a significant decrease in the activity or absence of the enzyme α-galactosidase A. The diagnostics of Fabry disease during newborn screening are reasonable, due to the availability of enzyme replacement therapy. This paper presents an electrochemical method using complementary metal-oxide semiconductor (CMOS)-compatible ion-sensitive field effect transistors (ISFETs) with hafnium oxide-sensitive surfaces for the detection of α-galactosidase A activity in dried blood spot extracts. The capability of ISFETs to detect the reaction catalyzed by α-galactosidase A was demonstrated. The buffer composition was optimized to provide suitable conditions for both enzyme and ISFET performance. The use of ISFET structures as sensor elements allowed for the label-free detection of enzymatic reactions with melibiose, a natural substrate of α-galactosidase A, instead of a synthetic fluorogenic one. ISFET chips were packaged with printed circuit boards and microfluidic reaction chambers to enable long-term signal measurement using a custom device. The packaged sensors were demonstrated to discriminate between normal and inhibited GLA activity in dried blood spots extracts. The described method offers a promising solution for increasing the widespread distribution of newborn screening of Fabry disease. [ABSTRACT FROM AUTHOR]

المؤلفون: Tsap, Mariana I.¹, Yatsenko, Andriy S.¹, Hegermann, Jan², Beckmann, Bibiana³, Tsikas, Dimitrios³, Shcherbata, Halyna R.^1,4 Shcherbata.Halyna@mhhannover.de

المصدر: eLife. 5/13/2024, p1-34. 34p.

مصطلحات موضوعية: *LYSOSOMAL storage diseases, *BLOOD-brain barrier, *FATTY acids, *INFLAMMATION, *METABOLISM, *ANTI-inflammatory agents

مستخلص: Mutations in Drosophila Swiss cheese (SWS) gene or its vertebrate orthologue neuropathy target esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration. [ABSTRACT FROM AUTHOR]

المؤلفون: Muñoz-Oreja, Mikel^1,2,3 (AUTHOR), Sandoval, Abigail⁴ (AUTHOR), Bruland, Ove⁵ (AUTHOR), Perez-Rodriguez, Diego⁶ (AUTHOR), Fernandez-Pelayo, Uxoa¹ (AUTHOR), Arbina, Amaia Lopez de¹ (AUTHOR), Villar-Fernandez, Marina¹ (AUTHOR), Hernández-Eguiazu, Haizea¹ (AUTHOR), Hernández, Ixiar² (AUTHOR), Park, Yohan⁴ (AUTHOR), Goicoechea, Leire^7,8,9 (AUTHOR), Pascual-Frías, Nerea^1,10 (AUTHOR), Garcia-Ruiz, Carmen^7,8,9 (AUTHOR), Fernandez-Checa, Jose^7,8,9,11 (AUTHOR), Martí-Carrera, Itxaso^1,2,3,12 (AUTHOR), Gil-Bea, Francisco Javier¹ (AUTHOR), Hasan, Mazahir T^13,14 (AUTHOR), Gegg, Matthew E⁶ (AUTHOR), Bredrup, Cecilie^15,16 (AUTHOR), Knappskog, Per-Morten¹⁷ (AUTHOR)

المصدر: Brain: A Journal of Neurology. May2024, Vol. 147 Issue 5, p1899-1913. 15p.

مصطلحات موضوعية: *LYSOSOMAL storage diseases, *CHOLESTEROL, *CHOLESTEROL metabolism, *CELL membranes, *GLYCOGEN storage disease type II

مستخلص: Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3 , which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. By subjecting the Drosophila Atad3 mutant to nutrient restriction and cholesterol supplementation, we show that the mutant displays heightened cholesterol dependence. Collectively, these findings suggest that elevated cholesterol enhances tolerance to pathological ATAD3 variants; however, this comes at the cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates. [ABSTRACT FROM AUTHOR]

المؤلفون: Farhat, Nicole Y.¹ (AUTHOR) nicole.farhat@nih.gov, Alexander, Derek¹ (AUTHOR) derek.alexander@nih.gov, McKee, Kyli¹ (AUTHOR) kyli.a.mckee@gmail.com, Iben, James² (AUTHOR) james.iben@nih.gov, Rodriguez-Gil, Jorge L.³ (AUTHOR) jrgil@stanford.edu, Wassif, Christopher A.¹ (AUTHOR) christopher.wassif@astrazeneca.com, Cawley, Niamh X.¹ (AUTHOR) cawleyn@mail.nih.gov, Balch, William E.⁴ (AUTHOR) webalch@scripps.edu, Porter, Forbes D.¹ (AUTHOR) fdporter@mail.nih.gov

المصدر: International Journal of Molecular Sciences. Apr2024, Vol. 25 Issue 8, p4217. 14p.

مصطلحات موضوعية: *NIEMANN-Pick diseases, *LYSOSOMAL storage diseases, *GENE expression, *NATURAL history, *AGE of onset

مستخلص: Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment. Marked heterogeneity has been observed in individuals with the same NPC1 genotype, thus suggesting a significant effect of modifier genes. Prior work demonstrated that decreased SOAT1 activity decreased disease severity in an NPC1 mouse model. Thus, we hypothesized that a polymorphism associated with decreased SOAT1 expression might influence the NPC1 phenotype. Phenotyping and genomic sequencing of 117 individuals with NPC1 was performed as part of a Natural History trial. Phenotyping included determination of disease severity and disease burden. Significant clinical heterogeneity is present in individuals homozygous for the NPC1I1061T variant and in siblings. Analysis of the SOAT1 polymorphism, rs1044925 (A>C), showed a significant association of the C-allele with earlier age of neurological onset. The C-allele may be associated with a higher Annualized Severity Index Score as well as increased frequency of liver disease and seizures. A polymorphism associated with decreased expression of SOAT1 appears to be a genetic modifier of the NPC1 phenotype. This finding is consistent with prior data showing decreased phenotypic severity in Npc1-/-:Soat1-/- mice and supports efforts to investigate the potential of SOAT1 inhibitors as a potential therapy for NPC1. [ABSTRACT FROM AUTHOR]

المؤلفون: Li, Joyce Wai-Yin¹ (AUTHOR), Yan, Kevin¹ (AUTHOR), Balijepalli, Chakrapani¹ (AUTHOR), Druyts, Eric¹ (AUTHOR) eric.druyts@pharmalyticsgroup.com

المصدر: Current Medical Research & Opinion. Apr2024, Vol. 40 Issue 4, p709-722. 14p.

مصطلحات موضوعية: *LYSOSOMAL storage diseases, *SOCIAL skills, *GLYCOGEN storage disease type II

مستخلص: To systematically review the literature and summarize the health-related quality-of-life (HRQoL) of patients undergoing treatment for mucopolysaccharidoses (MPS), a rare, hereditary lysosomal storage disorder. A systematic review was performed in accordance with PRISMA guidelines to identify research studies that describe the humanistic burden of MPS. A comprehensive literature search was conducted in EMBASE, MEDLINE, and eligible conferences were screened to include applicable abstracts. Of 870 identified articles, 15 studies reported the HRQoL burden of patients with MPS undergoing or with a history of ERT and/or HSCT. These studies include patients of MPS I (n = 2), MPS II (n = 4), MPS IV (n = 6), MPS VI (n = 1), and subtype not mentioned (n = 2). Although the quality-of-life of MPS patients is influenced by time of diagnosis, pain, cognitive involvement, severity of disease, mobility, dependence, and time of treatment initiation, the HRQoL scores of MPS patients across all the scales were below the median reference population scores across all dimensions. This is seen in comparison to healthy participants but also in comparison to patients with other chronic illnesses. The multi-organ involvement, neurological impairment, pain, and morbidity associated with the condition not only affects activity of daily living but also affects social functioning, emotional status, employment status among adults, and school functioning among children. This systematic literature review revealed the substantial humanistic burden of individuals affected by MPS as well as caregivers. Significant variation in HRQoL scores was observed, however studies indicate that the quality-of-life of MPS patients is influenced primarily by severity of disease (MPS type and phenotype), and then by time of diagnosis, pain, cognitive involvement, mobility, dependence, and time of treatment initiation. Further studies are needed to assess the global humanistic burden of MPS, particularly in MPS III, VI, VII, and IX subtypes, in adults, and for a longer follow-up period. Considering the vast array of HRQoL assessment tools available and used in this study, researchers should also consider using scales with condition-specific measures to ensure appropriate estimates of effectiveness. [ABSTRACT FROM AUTHOR]

المؤلفون: Huang, Guiwu^1,2,3 (AUTHOR), Jian, Jinlong^1,2 (AUTHOR), Liu, Chuan-Ju^1,2,4 (AUTHOR) chuan-ju.liu@yale.edu

المصدر: Cytokine & Growth Factor Reviews. Apr2024, Vol. 76, p142-159. 18p.

مصطلحات موضوعية: *PROGRANULIN, *LYSOSOMAL storage diseases, *PERIPHERAL nervous system, *PROTEIN microarrays, *MUSCULOSKELETAL system diseases, *DEGENERATION (Pathology)

مستخلص: Progranulin (PGRN), encoded by the GRN gene in humans, was originally isolated as a secreted growth factor that implicates in a multitude of processes ranging from regulation of tumorigenesis, inflammation to neural proliferation. Compelling evidence indicating that GRN mutation can lead to various common neuronal degenerative diseases and rare lysosomal storage diseases. These findings have unveiled a critical role for PGRN as a lysosomal protein in maintaining lysosomal function. The phenotypic spectrum of PGRN imbalance has expanded to encompass a broad spectrum of diseases, including autoimmune diseases, metabolic, musculoskeletal and cardiovascular diseases. These diseases collectively referred to as Progranulinopathy- a term encompasses the wide spectrum of disorders influenced by PGRN imbalance. Unlike its known extracellular function as a growth factor-like molecule associated with multiple membrane receptors, PGRN also serves as an intracellular co-chaperone engaged in the folding and traffic of its associated proteins, particularly the lysosomal hydrolases. This chaperone activity is required for PGRN to exert its diverse functions across a broad range of diseases, encompassing both the central nervous system and peripheral systems. In this comprehensive review, we present an update of the emerging role of PGRN in Progranulinopathy, with special focus on elucidating the intricate interplay between PGRN and a diverse array of proteins at various levels, ranging from extracellular fluids and intracellular components, as well as various pathophysiological processes involved. This review seeks to offer a comprehensive grasp of PGRN's diverse functions, aiming to unveil intricate mechanisms behind Progranulinopathy and open doors for future research endeavors. [Display omitted] • Progranulin is involved in processes ranging from tumorigenesis and inflammation to neural proliferation. • Mutations in the GRN gene can result in various neuronal degenerative diseases and rare lysosomal storage disorders. • The range of conditions and diseases stemming from PGRN imbalance collectively termed as Progranulinopathy. • Beyond recognized role as an extracellular growth factor-like molecule, PGRN also operates as an intracellular co-chaperone. • This review delves into the complex interplay between PGRN and an assorted array of proteins across different tiers. [ABSTRACT FROM AUTHOR]

المؤلفون: Servín Muñoz, Iris Valeria¹ (AUTHOR) iris.servin@alumnos.udg.mx, Ortuño-Sahagún, Daniel¹ (AUTHOR) daniel.ortuno@academicos.udg.mx, Griñán-Ferré, Christian^2,3 (AUTHOR) christian.grinan@ub.edu, Pallàs, Mercè^2,3 (AUTHOR) pallas@ub.edu, González-Castillo, Celia⁴ (AUTHOR) daniel.ortuno@academicos.udg.mx

المصدر: International Journal of Molecular Sciences. Apr2024, Vol. 25 Issue 7, p3806. 17p.

مصطلحات موضوعية: *LYSOSOMAL storage diseases, *HISTONE deacetylase inhibitors, *MUTANT proteins, *PROTEIN folding, *ALZHEIMER'S disease

مستخلص: Niemann–Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and β-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process. [ABSTRACT FROM AUTHOR]

المؤلفون: Álvarez, J. Victor.^1,2 (AUTHOR) jose.victor.alvarez.gonzalez@sergas.es, Bravo, Susana B.³ (AUTHOR) sbbravo@gmail.com, Chantada-Vázquez, María Pilar³ (AUTHOR) mariadelpilarchantadavazquez@gmail.com, Pena, Carmen³ (AUTHOR) carmen.pena.pena@sergas.es, Colón, Cristóbal^1,2 (AUTHOR) cristobal.colon.mejeras@sergas.es, Tomatsu, Shunji⁴ (AUTHOR) stomatsu@nemours.org, Otero-Espinar, Francisco J.^5,6 (AUTHOR) francisco.otero@usc.es, Couce, María L.^1,2 (AUTHOR) maria.luz.couce.pico@sergas.es

المصدر: International Journal of Molecular Sciences. Mar2024, Vol. 25 Issue 6, p3232. 28p.

مصطلحات موضوعية: *MOLECULAR interactions, *LYSOSOMAL storage diseases, *KNOCKOUT mice, *ENZYME deficiency, *REACTIVE oxygen species, *LACTATE dehydrogenase, *SULFATASES, *BLOOD coagulation factor XIII

مستخلص: Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disease (LSD) caused by deficiency of a hydrolase enzyme, N-acetylgalactosamine-6-sulfate sulfatase, and characterized clinically by mainly musculoskeletal manifestations. The mechanisms underlying bone involvement in humans are typically explored using invasive techniques such as bone biopsy, which complicates analysis in humans. We compared bone proteomes using DDA and SWATH-MS in wild-type and MPS IVA knockout mice (UNT) to obtain mechanistic information about the disease. Our findings reveal over 1000 dysregulated proteins in knockout mice, including those implicated in oxidative phosphorylation, oxidative stress (reactive oxygen species), DNA damage, and iron transport, and suggest that lactate dehydrogenase may constitute a useful prognostic and follow-up biomarker. Identifying biomarkers that reflect MPS IVA clinical course, severity, and progression have important implications for disease management. [ABSTRACT FROM AUTHOR]