Abstract
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.
Highlights
Gaucher disease (GD) is caused by mutations in GBA1-encoding acid β-glucosidase (GCase, EC3.2.1.45), the lysosomal enzyme responsible for degradation of the glycosphingolipids, glucosylceramide (GC), and glucosylsphingosine (GS), a deacylated form of GC [1]
VDAC level (Figure 2G,H) were significantly reduced in Gba-/- neurons. These results demonstrate that impaired mitochondrial function in Gba-/- neurons can be modulated and improved by Substrate reduction therapy (SRT) treatment
The effect of SRT using GZ452 in central nervous system (CNS) was demonstrated by reduction in substrate accumulation in the brain [21] as well as improved neurological function and prolonged lifespan in mouse models of Neuronopathic GD (nGD) [22]
Summary
Gaucher disease (GD) is caused by mutations in GBA1-encoding acid β-glucosidase (GCase, EC3.2.1.45), the lysosomal enzyme responsible for degradation of the glycosphingolipids, glucosylceramide (GC), and glucosylsphingosine (GS), a deacylated form of GC [1]. The prevalence of GD in general population is ~1/60,000, and in the Ashkenazi. Jewish population it is 1 in 450. 1, GD1) or neuronopathic (Type 2, GD2 and Type 3, GD3) diseases depending on the clinical manifestations [2,3]. GD2 is an acute, rapidly progressive currently untreatable neonatal or early post-natal central nervous system (CNS) degenerative disease leading to death by 2 years of age [7]. GD3 is a subacute CNS and visceral disease presenting a highly variable phenotype ranging from progressive CNS disease early in childhood to adulthood, with death caused by currently untreatable CNS disease [8].
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