Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle...

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• Mutations in glucocerebrosidase (GCase) cause Gaucher disease and are a major risk factor for Parkinson's disease.
• Restoring GCase function in the brain is crucial for treating associated neurological disorders.
• Developing effective brain-targeted therapies remains a significant challenge.

Purpose of the Study:

• To engineer blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties to GCase (GCase-BS).
• To evaluate the efficacy of GCase-BS in cellular and animal models of GBA1-associated lysosomal dysfunction.

Main Methods:

• Development of GCase-BS fusion proteins.
• Assessment of cellular uptake and lysosomal efficiency of GCase-BS.
• Analysis of GCase-BS therapeutic effects in cellular disease models.
• Evaluation of GCase-BS efficacy in a mouse model, including biomarker analysis.

Main Results:

• GCase-BS demonstrated significantly increased cellular uptake and lysosomal efficiency compared to GCase alone.
• GCase-BS rapidly rescued lysosomal proteome and lipid accumulations in cellular models.
• Intravenous GCase-BS administration in mice led to sustained reduction of glucosylsphingosine.
• GCase-BS treatment in mice showed a potential to lower neurofilament-light chain plasma levels.

Conclusions:

• GCase-BS fusion proteins show significant potential for treating GBA1-associated lysosomal dysfunction.
• These findings highlight GCase-BS as a promising therapeutic strategy for neurological aspects of lysosomal storage diseases.
• The study provides insights into candidate biomarkers for treatment efficacy.