Altered Gene Expression in Prefrontal Cortex of a Fabry Disease Mouse Model

Abstract

Fabry disease is an X-chromosome linked hereditary disease that is caused by loss of function mutations in the α-galactosidase A (α-Gal A) gene, resulting in defective glycolipid degradation and subsequent accumulation of globotriaosylceramide (Gb3) in different tissues, including vascular endothelial cells and neurons in the peripheral and central nervous system. We recently reported a differential gene expression profile of α-Gal A(−/0) mouse dorsal root ganglia, an established animal model of Fabry disease, thereby providing new gene targets that might underlie the neuropathic pain related symptoms. To investigate the cognitive symptoms experienced by Fabry patients, we performed one-color based hybridization microarray expression profiling of prefrontal cortex samples from adult α-Gal A(−/0) mice and age-matched wildtype controls, followed by protein-protein interaction and pathway analyses for the differentially regulated mRNAs. We found that from a total of 381 differentially expressed genes, 135 genes were significantly upregulated, whereas 246 genes were significantly downregulated between α-Gal A(−/0) mice and wildtype controls. Enrichment analysis for downregulated genes revealed mainly immune related pathways, including immune/defense responses, regulation of cytokine production, as well as signaling and transport regulation pathways. Further analysis of the regulated genes revealed a large number of genes involved in neurodegeneration. The current analysis for the first time presents a differential gene expression profile of central nervous system tissue from α-Gal A(−/0) mice, thereby providing novel knowledge on the deregulation and a possible contribution of gene expression to Fabry disease related brain pathologies.

Ion channels and pain in Fabry disease

“…In addition, most of the documented work in FD has focused on peripheral and spinal levels, while supraspinal structures should also be taken into account, especially since Gb3 accumulation has been also detected in different areas of the brain. 137…”

“…In addition, most of the documented work in FD has focused on peripheral and spinal levels, while supraspinal structures should also be taken into account, especially since Gb3 accumulation has been also detected in different areas of the brain. 137 Another aspect that should be considered is the effect on kidney function and its contribution to pain which is not consistently analyzed.…”

Neuropsychiatric Symptoms and Their Association With Sex, Age, and Enzyme Replacement Therapy in Fabry Disease: A Systematic Review

“…Increased oxidation stress attributed to the NOS secretion and production of the free radicals can cause vessel dilatation leading to changes in perfusion ( 49 ). Other molecular mechanisms, such as inflammation and altered gene expression, may play a role in the development of neuropsychiatric symptoms ( 50 – 52 ). ERT supplementation reduced inflammation markers in the musrine FD model ( 53 ).…”

Fabry Disease and Central Nervous System Involvement: From Big to Small, from Brain to Synapse

“…Another study explored neuronal gene expression changes in the prefrontal cortex in tissue samples from adult hemizygous AGA knock out male mice [ 61 ]. They performed mRNA microarray expression profiling, followed by qPCR validation and in-depth bioinformatics analyses of protein–protein interactions and pathways.…”