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

Abstract

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 knockout 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 in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (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 and 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 could be utilized to establish diagnostic and therapeutic strategies for fucosidosis.

Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice

“…Quantitative PCR analysis indicated decreased mRNA levels for Plp1 and MBP at 3 months of age, but we failed to observe significant changes in MBP level or immunoreactivity, suggesting sufficient MBP synthesis for myelination processes. Indications of neuron loss were not yet observed, as NeuN expression was unaltered, but have been reported in later stages of disease (Wolf et al, 2016 ).…”

“…Fuca1-deficient mice, a promising animal model for human fucosidosis, were shown to display a progressive disease course reminiscent of a milder form of the human condition (Wolf et al, 2016 ). The model exhibits pathognomonic CNS pathology, including lysosomal storage, axonal spheroid formation, neuroinflammation and loss of Purkinje cells.…”

“…Fuca1-deficient mice were generated as described previously (Wolf et al, 2016 ). All experiments were performed in 3-month-old Fuca1-deficient and age-matched wildtype (WT) littermates Behavioral assessment was performed in 15 WT and 15 knockout (KO) mice (all females).…”

“…The pursuit for therapeutic efficacy is hampered by practical limitations of such large animal models. Fuca1-deficient mice were recently generated by gene targeting techniques, which present a more practical animal model to study pathogenic events and evaluate experimental therapeutics (Wolf et al, 2016 ). These mice completely lack α-L-fucosidase activity and develop widespread lysosomal storage pathology leading to progressive neurological symptoms similar to human fucosidosis.…”

Transcriptomic analysis of FUCA1 knock‐down in keratinocytes reveals new insights into the pathogenesis of fucosidosis skin lesions

“…Obtaining samples for functional studies has been challenging due to the inherent difficulty in finding affected individuals. A knock‐out mouse model of Fuca1 had lysosomal storage pathology affecting visceral organs such as the central nervous system, bladder, spleen and liver but was not affected by skin dysfunction …”