scholarly journals Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2286
Author(s):  
Yanyan Peng ◽  
Benjamin Liou ◽  
Yi Lin ◽  
Venette Fannin ◽  
Wujuan Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Gaucher Disease ◽  
Consumption Rate ◽  
Cell Model ◽  
Neuronal Cell ◽  
Underlying Mechanism ◽  
Substrate Reduction Therapy ◽  
Substrate Reduction ◽  
A Cell ◽  
Mtorc1 Pathway

Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy–lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.

scholarly journals Long Term Follow-Up of 103 Untreated Adult Patients with Type 1 Gaucher Disease

2019 ◽  
Vol 8 (10) ◽  
pp. 1662 ◽  
Author(s):  
Dinur ◽  
Zimran ◽  
Becker-Cohen ◽  
Arkadir ◽  
Cozma ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Substrate Reduction Therapy ◽  
Type I ◽  
Specific Therapy ◽  
Substrate Reduction ◽  
Long Term Follow Up ◽  
Disease Specific

The introduction of disease-specific therapy for patients with type I Gaucher disease (GD1) was a revolution in the management of patients, but not without cost. Thus, the management of mildly affected patients is still debated. We herein report a long-term follow-up (median (range) of 20 (5–58) years) of 103 GD1 patients who have never received enzymatic or substrate reduction therapy. The median (range) platelet count and hemoglobin levels in last assessment of all but six patients who refused therapy (although recommended and approved) were 152 (56–408) × 103/mL and 13.1 (7.6–16.8) g/dL, respectively. Most patients had mild hepatosplenomegaly. Nine patients were splenectomized. No patient developed clinical bone disease. The median (range) lyso-Gb1 levels at last visit was 108.5 (8.1–711) ng/mL; lowest for patients with R496H/other and highest for patients refusing therapy. This rather large cohort with long follow-up confirms that mildly affected patients may remain stable for many years without GD-specific therapy. The challenge for the future, when newborn screening may detect all patients, is to be able to predict which of the early diagnosed patients is at risk for disease-related complications and therefore for early treatment, and who may remain asymptomatic or minimally affected with no need for disease-specific therapy.

Health outcomes research study on patients with type 1 Gaucher disease under substrate reduction therapy (SRT)

2017 ◽  
Vol 120 (1-2) ◽  
pp. S94
Author(s):  
Blanca Medrano Engay ◽  
Ana Roy ◽  
Koldo Atutxa ◽  
Vicente Diaz-Morant ◽  
Javier Garcia-Frade ◽  
...  
Keyword(s):  
Health Outcomes ◽  
Outcomes Research ◽  
Gaucher Disease ◽  
Research Study ◽  
Substrate Reduction Therapy ◽  
Health Outcomes Research ◽  
Substrate Reduction ◽  
Type 1 Gaucher Disease

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III

2008 ◽  
Vol 31 (6) ◽  
pp. 745-752 ◽  
Author(s):  
J. Cox-Brinkman ◽  
M. J. van Breemen ◽  
B. T. van Maldegem ◽  
L. Bour ◽  
W. E. Donker ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Disease Type ◽  
Substrate Reduction Therapy ◽  
Type Iii ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Potential Efficacy

Gaucher Disease

2016 ◽  
Author(s):  
Carla E.M. Hollak
Keyword(s):  
Bone Disease ◽  
Gaucher Disease ◽  
Severe Disease ◽  
Substrate Reduction Therapy ◽  
Disease Treatment ◽  
Enzyme Replacement ◽  
Rare Cancers ◽  
Substrate Reduction ◽  
Associated Conditions

Gaucher disease is frequently diagnosed in adulthood and may manifest at any age. Chronic neuronopathic forms are rarely seen but may come to the attention of the adult physician. Nonneuronopathic or type 1 disease is extremely variable. Main symptoms are cytopenia, hepatosplenomegaly and bone disease. The majority of patients diagnosed in adulthood present with thrombocytopenia and splenomegaly. In moderate to severe disease, treatment with intravenous enzyme replacement is highly effective. Substrate reduction therapy with miglustat or eliglustat is an oral alternative for some. Awareness of a number of severe complications and associated conditions, including irreversible bone disease, rare cancers and Parkinson's disease, is of importance.

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