An in-silico approach to studying a very rare neurodegenerative disease using a disease with higher prevalence with shared pathways and genes: Cerebral adrenoleukodystrophy and Alzheimer’s disease

Abstract

Cerebral adrenoleukodystrophy (cALD) is a rare neurodegenerative disease characterized by inflammatory demyelination in the central nervous system. Another neurodegenerative disease with a high prevalence, Alzheimer’s disease (AD), shares many common features with cALD such as cognitive impairment and the alleviation of symptoms by erucic acid. We investigated cALD and AD in parallel to study the shared pathological pathways between a rare disease and a more common disease. The approach may expand the biological understandings and reveal novel therapeutic targets. Gene set enrichment analysis (GSEA) and weighted gene correlation network analysis (WGCNA) were conducted to identify both the resemblance in gene expression patterns and genes that are pathologically relevant in the two diseases. Within differentially expressed genes (DEGs), GSEA identified 266 common genes with similar up- or down-regulation patterns in cALD and AD. Among the interconnected genes in AD data, two gene sets containing 1,486 genes preserved in cALD data were selected by WGCNA that may significantly affect the development and progression of cALD. WGCNA results filtered by functional correlation via protein–protein interaction analysis overlapping with GSEA revealed four genes (annexin A5, beta-2-microglobulin, CD44 molecule, and fibroblast growth factor 2) that showed robust associations with the pathogeneses of cALD and AD, where they were highly involved in inflammation, apoptosis, and the mitogen-activated protein kinase pathway. This study provided an integrated strategy to provide new insights into a rare disease with scant publicly available data (cALD) using a more prevalent disorder with some pathological association (AD), which suggests novel druggable targets and drug candidates.

iPSC-derived astrocytes to model phenotype-specific differential neuroinflammatory and metabolic responses in X-linked adrenoleukodystrophy

“…Furthermore, elevated neurotrophic factors such as ciliary neurotrophic factor in cALD may also signal through STAT3 and trigger reactive astrocytosis (Herrmann JE, 2008). STAT3 and CCL2 among the eight cluster genes were identified to share expression patterns in cALD and Alzheimer's disease; however, gene correlation network analysis pattern of AMN and Alzheimer's disease is not available (Shim YJ, 2022). Higher CCL2 observed in AMN astrocytes maybe protective by virtue of its role in microglial recruitment and regulating the immune system (Ueno et al, 2000).…”

Six mitophagy-related hub genes as peripheral blood biomarkers of Alzheimer’s disease and their immune cell infiltration correlation

“…It has been suggested that the three genes CD44 , ITGAX , and PPARG participate in AD pathogenesis mainly through neuroinflammation and immune pathways, making them promising therapeutic targets. Previous studies have shown that CD44 may be highly involved in biological processes and pathways related to immune inflammatory response, apoptosis, and mitogen-activated protein kinase pathways in AD ( Shim et al, 2022 ; Xu et al, 2022 ). A systematic review found that CD44 is related to the complexity of reactive astrocytosis in AD ( Viejo et al, 2022 ).…”