New Directions in Gaucher Disease.

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• Gaucher disease (GD) results from deficient lysosomal acid β-glucocerebrosidase, causing glucosylceramide accumulation.
• GD presents with phenotypic heterogeneity, classified into non-neuronopathic (Type 1) and neuronopathic (Types 2 and 3) forms.
• Neuronopathic GD involves the central nervous system, potentially causing neuroinflammation and cell death, while Type 1 GD is linked to Parkinson disease (PD).

Purpose of the Study:

• To review the molecular and cellular mechanisms connecting Gaucher disease and Parkinson disease.
• To examine the clinical and genetic associations between GD and PD.
• To discuss current and potential treatment strategies for GD and its link to PD.

Main Methods:

• Literature review focusing on molecular, cellular, clinical, and genetic aspects of GD and PD.
• Analysis of enzyme transport, endoplasmic reticulum stress, and the Unfolded Protein Response in GD.
• Discussion of induced pluripotent stem cells (iPSCs) in understanding GD-PD associations.

Main Results:

• Mutant enzyme misfolding in the ER triggers the Unfolded Protein Response, contributing to GD pathogenesis.
• PD prevalence is notably higher in GD patients and carriers, suggesting a shared underlying mechanism.
• The review synthesizes current knowledge on GD-PD links, highlighting areas for therapeutic development.

Conclusions:

• The endoplasmic reticulum stress pathway is a key mediator in the association between Gaucher disease and Parkinson disease.
• Understanding the GD-PD connection offers insights into protein misfolding disorders and potential therapeutic targets.
• Induced pluripotent stem cells hold promise for modeling and investigating these complex neurological associations.