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Author ORCID Identifier

https://orcid.org/0000-0001-9144-7315

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2021

Month Degree Awarded

May

First Advisor

Scott Garman

Subject Categories

Biochemistry | Molecular Biology | Structural Biology

Abstract

Human lysosomal neuraminidase 1 (hNEU1) is an exo-a-sialidase which cleaves a(2-3) and a(2-6) linked sialic acids on glycoproteins in the lysosome. Deficiency of hNEU1 in the lysosome results in sialidosis, a lysosomal storage disease. Currently there is no effective treatment for sialidosis, which leads to a rising interest in discovering potential therapies. Here we presented a small molecule, α-D-N-acetylneuraminic acid (NANA), increases the protein amount and activity of both wild-type hNEU1 and three different hNEU1 mutations found in sialidosis patients in our mammalian cell system, suggesting that NANA works as a potential pharmacological chaperone for hNEU1 and provides a good scaffold for the development of pharmacological chaperone therapy for sialidosis. We also compared NANA with two potential treatments for sialidosis using MG132, a small molecule proteostasis regulator, or lysosomal protective protein/cathepsin A (PPCA), an auxiliary protein for hNEU1, and demonstrated that using MG132 or PPCA with NANA as potential combined treatments for sialidosis can enhance the enzymatic activity of hNEU1 in mammalian cells.

DOI

https://doi.org/10.7275/22496871.0

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