Gaucher disease – more than just a rare lipid storage disease

Roh, Jaehyeok; Subramanian, Subbaya; Weinreb, Neal J.; Kartha, Reena V.

doi:10.1007/s00109-021-02174-z

Cited by 21 publications

(17 citation statements)

References 229 publications

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“… 208400 613228 AGA aspartylglucosamini-dase [ 10 , 53 ] Gaucher disease (lysosome storage disorder) Multisystem Hepatosplenomegaly, bone pain or osteoporosis, anemia, thrombocytopenia, and in severe sub-types; hypotonia, dysphagia, respiratory failure, cardiac and neurological complications. 230800 230900 231000 231005 608013 606463 610539 176801 GBA1 PSAP glucosylceramidase beta 1 prosaposin [ 54 , 55 , 56 ] [ 57–61 ] Niemann-Pick disease type C1 (NPC) (lysosome storage disorder) Multisystem Clinically heterogeneous including visceromegaly, cholestasis and jaundice, lung complications, hypotonia, vertical supranuclear gaze palsy, hearing loss, ataxia, dysarthria, dysphagia, cognitive impairment, cataplexy, dystonia. 257220 607623 NPC1 NPC intracellular cholesterol transporter 1 Decreased expression of the sugar transporter SPNS1 (sphingolipid transporter 1 (putative)), which reduces MTOR reactivation during autophagy.…”

Section: The Involvement Of Autophagic Lysosome Reformation Defects I...mentioning

confidence: 99%

Autophagic lysosome reformation in health and disease

et al. 2022

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Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded. Autophagy cannot proceed without the sufficient generation of lysosomes, and this can be achieved via their de novo biogenesis. Alternatively, during autophagic lysosome reformation (ALR), lysosomes are generated via the recycling of autolysosome membranes. During this process, autolysosomes undergo significant membrane remodeling and scission to generate membrane fragments, that mature into functional lysosomes. By utilizing membranes already formed during autophagy, this facilitates an efficient pathway for re-deriving lysosomes, particularly under conditions of prolonged autophagic flux. ALR dysfunction is emerging as an important disease mechanism including for neurodegenerative disorders such as hereditary spastic paraplegia and Parkinson disease, neuropathies including Charcot-Marie-Tooth disease, lysosome storage disorders, muscular dystrophy, metabolic syndrome, and inflammatory and liver disorders. Here, we provide a comprehensive review of ALR, including an overview of its dynamic spatiotemporal regulation by MTOR and phosphoinositides, and the role ALR dysfunction plays in many diseases.

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Section: The Involvement Of Autophagic Lysosome Reformation Defects I...mentioning

confidence: 99%

Autophagic lysosome reformation in health and disease

et al. 2022

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“…GD is a rare hereditary lysosomal storage disorder caused by defects in the GBA1 gene ( 7 ). Splenomegaly, bone disease, and thrombocytopenia are the most common characteristics of GD ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

The molecular mechanism of Gaucher disease caused by compound heterozygous mutations in GBA1 gene

et al. 2023

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Gaucher disease (GD, ORPHA355) is a rare autosomal recessive genetic disease caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). Here, we report a patient with GD who carried the heterozygous c.1240G > C (p.Val414Leu) mutation and the heterozygous pathogenic c.1342G > C (p.Asp448His) mutation in GBA1. Bioinformatics analysis suggested that the two mutations are pathogenic. Functional studies showed that GBA1 mRNA and GCase protein levels of mutant types were significantly less than the wild-type. In the cell lysates, the two mutations of GBA1 c.1240G > C and c.1342G > C caused a decreased GCase concentration, while the two mutations did not change the distribution in the cell. The pathogenicity of the compound heterozygous mutations was verified. Early diagnosis and treatment can improve the quality of life and prevent unnecessary procedures in patients with GD.

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“…One possible mechanism of sclerostin elevation in GD is that functional lysosome is essential for sclerostin degradation ( 46 ). However, in GD, accumulation of GC in lysosomes leads to impaired autophagy-lysosomal function, activating the endoplasmic reticulum (ER)-associated degradation pathway and the unfolded protein response ( 47 – 52 ). Thus, sclerostin degradation may be compromised in GD.…”

Section: Discussionmentioning

confidence: 99%

Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease

et al. 2022

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Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson’s linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.

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Gaucher disease – more than just a rare lipid storage disease

Cited by 21 publications

References 229 publications

Autophagic lysosome reformation in health and disease

Autophagic lysosome reformation in health and disease

The molecular mechanism of Gaucher disease caused by compound heterozygous mutations in GBA1 gene

Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease

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