Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice

Abstract

Fucosidosis is a lysosomal storage disorder (LSD) caused by lysosomal α-L-fucosidase deficiency. Insufficient α-L-fucosidase activity triggers accumulation of undegraded, fucosylated glycoproteins and glycolipids in various tissues. The human phenotype is heterogeneous, but progressive motor and cognitive impairments represent the most characteristic symptoms. Recently, Fuca1-deficient mice were generated by gene targeting techniques, constituting a novel animal model for human fucosidosis. These mice display widespread LSD pathology, accumulation of secondary storage material and neuroinflammation throughout the brain, as well as progressive loss of Purkinje cells. Fuca1-deficient mice and control littermates were subjected to a battery of tests detailing different aspects of motor, emotional and cognitive function. At an early stage of disease, we observed reduced exploratory activity, sensorimotor disintegration as well as impaired spatial learning and fear memory. These early markers of neurological deterioration were related to the respective stage of neuropathology using molecular genetic and immunochemical procedures. Increased expression of the lysosomal marker Lamp1 and neuroinflammation markers was observed throughout the brain, but appeared more prominent in cerebral areas in comparison to cerebellum of Fuca1-deficient mice. This is consistent with impaired behaviors putatively related to early disruptions of motor and cognitive circuits particularly involving cerebral cortex, basal ganglia, and hippocampus. Thus, Fuca1-deficient mice represent a practical and promising fucosidosis model, which can be utilized for pathogenetic and therapeutic studies.

Glycan degradation promotes macroautophagy

“…We next examined if loss of FUCA1 was associated with changes in tissue architecture. Consistent with previous studies on fucosidosis ( 19 , 20 ), histological analysis revealed prominent cytoplasmic vacuolation in a variety of tissues with marked effects in neurons and glia in the central nervous system, hepatocytes in the liver, acinar cells in the pancreas, and the kidney ( Fig. 1 E ).…”

“…Although the principal aim of our study was to understand the importance of glycan breakdown in macroautophagy, our study also yields significant insights regarding the etiology of fucosidosis. Behavioral characterization of Fuca1 −/− mice revealed deficiencies in motor function and reduced exploration over time (habituation), characteristics consistent with a neurodegenerative phenotype as seen in fucosidosis patients and in a previous mouse model of the disease ( 20 ). Importantly we show, as has been reported for other lysosomal storage disorders, that the accumulation of lysosomal material in fucosidosis can be attributed to a defect in macroautophagy ( 42 , 43 ).…”

Fucosidosis—Clinical Manifestation, Long-Term Outcomes, and Genetic Profile—Review and Case Series

“…The authors demonstrated behavioral alterations in Fuca1-deficient mice that coincided with early signs of neuropathology (at 3 months of age); subtle abnormalities in sensorimotor and cognitive abilities were identified. The animals displayed lysosomal dysregulation (increased Lamp1 expression) and evidence of neuroinflammation and secondary storage of GM2 ganglioside, as early manifestations of brain pathology [ 85 ]. These abnormalities preceded neuron loss but imply an early stage of neuropathology encompassing an extended endosomal-lysosomal network, secondary lipid storage, and emerging microgliosis and astrogliosis [ 86 ].…”

Emerging cellular themes in leukodystrophies

“…Because these defects were observed during developmental stages, they support a mechanism of hypomyelination rather than demyelination ( Fletcher et al, 2011 ; 2014). In addition, a Fuca1 knockout mouse exhibited lysosomal dysregulation, lipid accumulation, neuroinflammation, and behavioral deficits (e.g., impaired coordination and spatial learning) that parallel the motor and intellectual deficits observed in fucosidosis patients ( Stroobants et al, 2018 ). Thus, both canine and murine disease models indicate that many downstream effects of FUCA1 deficiency contribute to myelin defects in fucosidosis.…”