Authors:

Sneha Guha

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About Paper:

Parkinson's disease (PD) is a neurological disorder characterized by the loss of dopaminergic neurons resulting in movement disorders and dementia. A key contributor to disease progression is the aggregation of a-synuclein, which is exacerbated in some PD patients by mutations in the GBA gene that encodes for the Glucosylceramidase (GCase) enzyme. Mutations in GBA impair GCase function, resulting in lipid accumulation that accelerates alpha-synuclein aggregation and neuronal degeneration. Enzyme replacement therapy (ERT), which introduces functional proteins to restore enzymatic activity, can be a promising strategy. However, delivering protein to the brain is challenging due to the blood-brain barrier (BBB), which limits uptake of macromolecules. Protein spherical nucleic acids (ProSNAs), characterized by a dense shell of oligonucleotides on the surface, have shown promise in enhancing cellular uptake while maintaining protein function. Previous studies dernonstrated that ProSNA with Transferrin (Tfr) aptamer enhanced protein uptake to the brain [1]. Given folate receptors are also abundant in the central nervous system (CNS), we hypothesized that dual targeting GCase protein with folic acid and Tfr would increase receptor mediated transcytosis. We synthesized four different GCase spherical nucleic acids (GCase-ProSNA) and tested their activity and uptake in different BBB cells. We found that the Tfr ProSNAs, and the bivalent ProSNAs showed highest uptake and enzymatic activity compared to other variants and controls. These findings indicate that GCase ProSNAs can be a promising strategy for enzyme delivery across the BBB, offering potential therapeutic benefit for PD and other neurodegenerative diseases.

Source:

Northwestern University

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Co-authors:

Sneha Guha