Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice.

[fabry disease]

Mutations in the gene for alpha-galactosidase A result in Fabry disease , a rare , X-linked lysosomal storage disorder characterized by a loss of alpha-galactosidase A enzymatic activity . The resultant accumulation of glycosphingolipids throughout the body leads to widespread vasculopathy with particular detriment to the kidneys , heart and nervous system . Disruption in the autophagy-lysosome pathway has been documented previously in Fabry disease but its relative contribution to nervous system pathology in Fabry disease is unknown . Using an experimental mouse model of Fabry disease , alpha-galactosidase A deficiency , we examined brain pathology in 20 -24 month old mice with particular emphasis on the autophagy-lysosome pathway .Alpha -galactosidase A-deficient mouse brains exhibited enhanced punctate perinuclear immunoreactivity for the autophagy marker microtubule-associated protein light-chain 3 (LC 3 ) in the parenchyma of several brain regions , as well as enhanced parenchymal and vascular immunoreactivity for lysosome-associated membrane protein-1 (LAMP-1 ). Ultrastructural analysis revealed endothelial cell inclusions with electron densities and a pronounced accumulation of electron-dense lipopigment . The pons of alpha-galactosidase A-deficient mice in particular exhibited a striking neuropathological phenotype , including the presence of large , swollen axonal spheroids indicating axonal degeneration , in addition to large interstitial aggregates positive for phosphorylated alpha-synuclein that co -localized with the axonal spheroids . Double -label immunofluorescence revealed co -localization of phosphorylated alpha-synuclein aggregates with ubiquitin and LC 3 .Together these findings indicate widespread neuropathology and focused axonal neurodegeneration in alpha-galactosidase A-deficient mouse brain in association with disruption of the autophagy-lysosome pathway , and provide the basis for future mechanistic assessment of the contribution of the autophagy-lysosome pathway to this histologic phenotype .

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Diseases presenting "alpha-galactosidase a deficiency" symptom

fabry disease

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