 Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle constructAlexandra Gehrlein (),
Vinod Udayar,
Nadia Anastasi,
Martino L. Morella,
Iris Ruf,
Doris Brugger,
Sophia Mark,
Ralf Thoma,
Arne Rufer,
Dominik Heer,
Nina Pfahler,
Anton Jochner,
Jens Niewoehner,
Luise Wolf,
Matthias Fueth,
Martin Ebeling,
Roberto Villaseñor,
Yanping Zhu,
Matthew C. Deen,
Xiaoyang Shan,
Zahra Ehsaei,
Verdon Taylor,
Ellen Sidransky,
David J. Vocadlo,
Per-Ola Freskgård and
Ravi Jagasia ()
Nature Communications, 2023, vol. 14, issue 1, 1-21 Abstract: Abstract Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Therapies to restore the enzyme’s function in the brain hold great promise for treating the neurological implications. Thus, we developed blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties to β-glucocerebrosidase (referred to as GCase-BS). We demonstrate that these fusion proteins show significantly increased uptake and lysosomal efficiency compared to the enzyme alone. In a cellular disease model, GCase-BS rapidly rescues the lysosomal proteome and lipid accumulations beyond known substrates. In a mouse disease model, intravenous injection of GCase-BS leads to a sustained reduction of glucosylsphingosine and can lower neurofilament-light chain plasma levels. Collectively, these findings demonstrate the potential of GCase-BS for treating GBA1-associated lysosomal dysfunction, provide insight into candidate biomarkers, and may ultimately open a promising treatment paradigm for lysosomal storage diseases extending beyond the central nervous system. Date: 2023 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37632-4 Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-023-37632-4 Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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