PROGRESSIVE NEURODEGENERATION IN ASPARTYLGLYCOSAMINURIA MICE

Aspartylglycosaminuria (AGU) is one of the most common lysosomal stora ge disorders in humans. A mouse model for AGU has been recently genera ted through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated m any pathological changes found in human AGU patients (Kaartinen V, Mon onen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mou se model for aspartylglycosaminuria, Nat Med 1996, 2:1375-1378). Our c urrent findings demonstrate that after the age of 10 months, the gener al condition of null mutant mice gradually deteriorated. They suffered from a progressive motoric impairment and impaired bladder function a nd died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. This neuronal vacuolation was particular ly severe in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nucle i. The oldest animals (20 months old) displayed a clear neuronal loss and gliosis, particularly in those regions, where the most severe vacu olation was found. The severe ataxic gait of the older mice was likely due to the dramatic loss of Purkinje cells, intensive astrogliosis an d vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impai red bladder function and subsequent hydronephrosis were secondary to i nvolvement of the central nervous system. These findings demonstrate t hat the glycosylasparaginase-deficient mice share many neuropathologic al features with human AGU patients, providing a suitable animal model to test therapeutic strategies in the treatment of the central nervou s system effects in AGU.