A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase ( Fuca1 ) was disrupted by gene targeting. Homozygous knock-out mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted with the urine. Lysosomal storage pathology was observed in many visceral organs like liver, kidney, spleen and bladder as well as in the CNS. On the cellular level storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material, neuroinflammation as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model may be utilized to establish diagnostic and therapeutic strategies for fucosidosis.