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Lysosomal sialidase NEU1, its intracellular properties, deficiency, and use as a therapeutic agent

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Abstract

Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic reticulum (RER) lumen as an N-glycosylated protein to associate with its protective protein/cathepsin A (CTSA) and then form a lysosomal multienzyme complex (LMC) also containing β-galactosidase 1 (GLB1). Unlike other mammalian sialidases, including NEU2 to NEU4, NEU1 transport to lysosomes requires association of NEU1 with CTSA, binding of the CTSA carrying terminal mannose 6-phosphate (M6P)-type N-glycan with M6P receptor (M6PR), and intralysosomal NEU1 activation at acidic pH. In contrast, overexpression of the single NEU1 gene in mammalian cells causes intracellular NEU1 protein crystallization in the RER due to self-aggregation when intracellular CTSA is reduced to a relatively low level. Sialidosis (SiD) and galactosialidosis (GS) are autosomal recessive lysosomal storage diseases caused by the gene mutations of NEU1 and CTSA, respectively. These incurable diseases associate with the NEU1 deficiency, excessive accumulation of sialylglycans in neurovisceral organs, and systemic manifestations. We established a novel GS model mouse carrying homozygotic Ctsa IVS6 + 1 g/a mutation causing partial exon 6 skipping with simultaneous deficiency of Ctsa and Neu1. Symptoms developed in the GS mice like those in juvenile/adult GS patients, such as myoclonic seizures, suppressed behavior, gargoyle-like face, edema, proctoptosis due to Neu1 deficiency, and sialylglycan accumulation associated with neurovisceral inflammation. We developed a modified NEU1 (modNEU1), which does not form protein crystals but is transported to lysosomes by co-expressed CTSA. In vivo gene therapy for GS and SiD utilizing a single adeno-associated virus (AAV) carrying modNEU1 and CTSA genes under dual promoter control will be created.

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Acknowledgements

We acknowledge the support of the Ministry of Education, Culture, Sports, Science and Technology (MEXT); the Japan Society for the Promotion of Science (JSPS), MEXT/JSPS KAKENHI (Grant No. 17H04102 to K.I.); and the Japan Agency for Medical Research and Development (AMED) (TR-SPRINT Seeds A, A098 to K.I.).

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  1. Department of Medicinal Biotechnology, Institute for Medicinal Biotechnology, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima, Japan

    Kohji Itoh & Jun Tsukimoto

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  1. Kohji Itoh
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  2. Jun Tsukimoto
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K.I. wrote the main manuscript text and J.T. prepared Figs. 1 and 2. All authors reviewed the manuscript.

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Correspondence to Kohji Itoh.

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This article does not contain any studies with human participants or animals performed by any of the authors. The animal experiments described in this journal were approved by the Tokushima University Animal Experiment Committee and conducted at the animal experiment facilities under the Animal Experiment Management Regulations of Tokushima University Japan.

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Itoh, K., Tsukimoto, J. Lysosomal sialidase NEU1, its intracellular properties, deficiency, and use as a therapeutic agent. Glycoconj J 40, 611–619 (2023). https://doi.org/10.1007/s10719-023-10135-6

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