title: Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Alpha-galactosidase A-deficient mouse brains exhibited enhanced punctate perinuclear immunoreactivity for the autophagy marker microtubule-associated protein light-chain 3 (LC3) 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 LC3.
  
  
  CONCLUSIONS
  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.
authors: Michael P
authors: MP
authors: Nelson
authors: Tonia E
authors: TE
authors: Tse
authors: Darrel B
authors: DB
authors: O'Quinn
authors: Stefanie M
authors: SM
authors: Percival
authors: Edgar A
authors: EA
authors: Jaimes
authors: David G
authors: DG
authors: Warnock
authors: Department Pathology, Neuropathology Division, University of Alabama at Birmingham, Birmingham, AL USA. shacka@uab.edu.
authors: John J
authors: JJ
authors: Shacka
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D002479:Inclusion Bodies / Q000473:pathology / Q000648:ultrastructure; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics; D061848:Optical Imaging; D015398:Signal Transduction / Q000235:genetics*; D000519:alpha-Galactosidase / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D000519:alpha-Galactosidase; D051844:alpha-Synuclein; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse