ArticleActa neuropathologica communications2014
Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice.
Article in Acta neuropathologica communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 66 citations in OpenAlex.
- Pathogenic mechanisms in Fabry disease.Frontiers in medicine · 2026Review
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- MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons.Biomedicines · 2024Article
- Inherited Metabolic Disorders: From Bench to Bedside.Biomedicines · 2024Article
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- Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy.The Journal of clinical investigation · 2023Article
- Fabry Disease and Central Nervous System Involvement: From Big to Small, from Brain to Synapse.International journal of molecular sciences · 2023Review
- Biochemical Mechanisms beyond Glycosphingolipid Accumulation in Fabry Disease: Might They Provide Additional Therapeutic Treatments?Journal of clinical medicine · 2023Review
- Anderson-Fabry Disease: A New Piece of the Lysosomal Puzzle in Parkinson Disease?Biomedicines · 2022Review
- Lysosomal positioning diseases: beyond substrate storage.Open biology · 2022Review
- Secondary Mitochondrial Dysfunction as a Cause of Neurodegenerative Dysfunction in Lysosomal Storage Diseases and an Overview of Potential Therapies.International journal of molecular sciences · 2022Review
- Autophagy-lysosome pathway alteration in ocular surface manifestations in Fabry disease patients.Orphanet journal of rare diseases · 2022Article
- p21-activated kinase 4 controls the aggregation of α-synuclein by reducing the monomeric and aggregated forms of α-synuclein: involvement of the E3 ubiquitin ligase NEDD4-1.Cell death & disease · 2022Article
- Structural disconnection and functional reorganization in Fabry disease: a multimodal MRI study.Brain communications · 2022Article
- Defects of Nutrient Signaling and Autophagy in Neurodegeneration.Frontiers in cell and developmental biology · 2022Review
- Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies.International journal of molecular sciences · 2021Review
- Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis.Kidney research and clinical practice · 2021Article
- Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders.Acta neuropathologica · 2021Review
- Reversal of the Inflammatory Responses in Fabry Patient iPSC-Derived Cardiovascular Endothelial Cells by CRISPR/Cas9-Corrected Mutation.International journal of molecular sciences · 2021Article
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7 authors at 2 institutions in 1 country.
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Abstract
backgroundMutations 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.
resultsAlpha-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.
conclusionTogether 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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