Lysosomal Neuraminidase 1 (NEU1): Its Unique Molecular Characters and Therapeutic Approaches for Deficiencies.

Neuraminidase 1 (NEU1) is a lysosomal sialidase that removes terminal α-bound sialic acid from sialylglycoconjugates and contributes to ubiquitous catabolism of sialylglycoconjugates and immunoregulatory functions. Different from other human sialidases, including NEU2 to NEU4, NEU1 is first produced as an N-glycosylated precursor protein, which binds to its protective protein/cathepsin A (CTSA) and then forms a lysosomal multienzyme complex (LMC) with β-galactosidase 1 (GLB1) in the rough endoplasmic reticulum (RER) lumen. NEU1 trafficking to lysosomes and intralysosomal activation under acidic pH conditions essentially requires association with CTSA, which carries terminal mannose 6-phosphate (M6P)-type N-glycan to bind with cation-dependent (CD) M6P receptor (CD-M6PR) in the Golgi apparatus via endosomes. In contrast, the single NEU1 gene overexpression in mammalian cells results in NEU1 protein crystallization in the RER owing to self-aggregation at a relatively low intrinsic CTSA level. Two NEU1 deficiencies, sialidosis (SiD) and galactosialidosis (GS), are caused by autosomal recessive NEU1 and CTSA gene mutations, respectively. These untreatable disorders are associated with excessive storage of sialylglycans in neurovisceral organs and systemic symptoms. We produced a new GS model mouse by introducing a homozygous Ctsa IVS6+1g/a mutation into the murine gene locus, leading to partial exon 6 skipping and simultaneous deficiency of Ctsa and Neu1. The GS mice exhibited clinical symptoms similar to those seen in juvenile/adult GS patients, including myoclonic seizures, suppressed behavior, a gargoyle-like face, edema, proctoptosis owing to Neu1 deficiency, and sialylglycan accumulation related to neurovisceral inflammation. Evaluating the efficacy of a novel therapy utilizing GS and SiD model mice and overcoming the human NEU1 gene product shortage will be necessary for a novel, effective treatment for NEU1 deficiencies.