In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers DISHEVELLED 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 Gaucher disease in vitro models.
Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic.
Gaucher disease is an inherited metabolic disease caused by genetic acid β -glucosidase (GBA) deficiency and is currently treated by enzyme replacement therapy.
This study provides novel pharmacokinetic data that support current imiglucerase administration regimens and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher disease type 1 aggressiveness.
Together, this comprehensive data set supports the treatment of adult and paediatric patients with GD who are naïve to ERT or who have previously been treated with imiglucerase.
These findings demonstrate that loss of GBA function may contribute to SNCA accumulation through inhibition of autophagy via PPP2A inactivation, thereby providing a mechanistic basis for the increased PD risk associated with GBA deficiency.
Loss of lysosomal glucocerebrosidase (GBA1) function is responsible for several organ defects, including skeletal abnormalities in type 1 Gaucher disease (GD).