Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid β-glucosidase residual activity levels

Abstract

Genetic and chemically induced neuronopathic mouse models of Gaucher disease were developed to facilitate understanding of the reversibility and/or progression of CNS involvement. The lethality of the skin permeability barrier defect of the complete gene knock out [gba, (glucocerebrosidase) GCase] was avoided by conditional reactivation of a low activity allele (D409H) in keratinocytes (kn-9H). In kn-9H mice, progressive CNS disease and massive glucosylceramide storage in tissues led to death from CNS involvement by the age of 14 days. Conduritol B epoxide (CBE, a covalent inhibitor of GCase) treatment (for 8-12 days) of wild type, D409H, D409V or V394L homozygotes recapitulated the CNS phenotype of the kn-9H mice with seizures, tail arching, shaking, tremor, quadriparesis, extensive neuronal degeneration loss and apoptosis, and death by the age of 14 days. Minor CNS abnormalities occurred after daily CBE injections of 100 mg/kg/day for 6 doses, but neuronal degeneration was progressive and glucosylceramide storage persisted in D409V homozygotes in the 2 to 5 months after CBE cessation; wild type and D409H mice had persistent neurological damage without progression. The persistent CNS deterioration, histologic abnormalities, and glucosylceramide storage in the CBE-treated D409V mice revealed a threshold level of GCase activity necessary for the prevention of progression of CNS involvement.

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

“…loss in the cerebrum and spinal cord 2-and 5-months after the final CBE injection despite recovery of GCase levels (67). These data suggest that it possible that lysosomal deficits caused by inhibiting GCase may be sufficient to cause progressive degeneration in the nigrostriatal pathway reminiscent of PD pathology.…”

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…The defi ciencies in neurotrophic factors (BDNF and NGF) cause sensory neuron degeneration in mice ( 214,215 ). These early abnormalities in lipid and neurotrophic factors correlated with substantial reductions in cellular density, neurodegeneration, and microglial infi ltration in Gba knockout mouse brains at E13-14 ( 149,150,208 ). Injection of the GCase inhibitor (cyclopellitol) early brain development ( Fig.…”

“…Also, substrate storage does not affect brain formation but does lead to early and severe degeneration of the brain and disruption of the skin permeability barrier ( 149,150 ). The downstream biological consequences of GlcCer and glucosylsphingosine accumulation are currently being investigated (see section III).…”

“…In this regard, the conditional experiments of Xu et al ( 150 ) are instructive. A chemically induced model of CNS Gaucher disease was produced by administering a covalent inhibitor, conduritol B epoxide (CBE), of GCase to neonatal mice ( 150 ). Wild-type and GCase point mutated mice were given daily injections of CBE from postnatal day 5 to day 11.…”

“…In such cases, one can envision the reestablishment of GSL fl ux in such cells might lead to recovery of their function and a positive effect on phenotype. In comparison, if the disease process has neuronal loss as a major pathogenic mechanism, recovery or even stabilization might be impossible; e.g., in neuronopathic Gaucher disease mice, neither complete enzyme reconstitution within neurons nor provision of microglia with wild-type GCase activity led to restoration or rescue of the CNS disease ( 150 ). Neuronal death is predominant in these models.…”