Abstract
Spastic ataxia (SA) is a group of rare neurodegenerative diseases, characterized by mixed features of generalized ataxia and spasticity. The pathogenetic mechanisms that drive the development of the majority of these diseases remain unclear, although a number of studies have highlighted the involvement of mitochondrial and lipid metabolism, as well as calcium signaling. Our group has previously published the GBA2 c.1780G > C (p.Asp594His) missense variant as the cause of spastic ataxia in a Cypriot consanguineous family, and more recently the biochemical characterization of this variant in patients’ lymphoblastoid cell lines. GBA2 is a crucial enzyme of sphingolipid metabolism. However, it is unknown if GBA2 has additional functions and therefore additional pathways may be involved in the disease development. The current study introduces bioinformatics approaches to better understand the pathogenetic mechanisms of the disease. We analyzed publicly available human gene expression datasets of diseases presented with ‘ataxia’ or ‘spasticity’ in their clinical phenotype and we performed pathway analysis in order to: (a) search for candidate perturbed pathways of SA; and (b) evaluate the role of sphingolipid signaling pathway and sphingolipid metabolism in the disease development, through the identification of differentially expressed genes in patients compared to controls. Our results demonstrate consistent differential expression of genes that participate in the sphingolipid pathways and highlight alterations in the pathway level that might be associated with the disease phenotype. Through enrichment analysis, we discuss additional pathways that are connected to sphingolipid pathways, such as PI3K-Akt signaling, MAPK signaling, calcium signaling, and lipid and carbohydrate metabolism as the most enriched for ataxia and spasticity phenotypes.
Highlights
Spastic ataxia (SA) is a term used to describe a group of rare neurodegenerative diseases of the central and peripheral nervous system, characterized by a combination of clinical features of cerebellar ataxias and spastic paraplegias
A total of 22 human microarray gene expression datasets derived from various tissues (Supplementary Material 1), were analyzed for the identification of differentially expressed genes (DEGs) in patients with ataxia or spasticity as described in the Materials and Methods
The results of differential expression analysis were used for the discovery of SA-related pathways, as well as for the evaluation of sphingolipid pathways as candidates for the development of the disease phenotype
Summary
Spastic ataxia (SA) is a term used to describe a group of rare neurodegenerative diseases of the central and peripheral nervous system, characterized by a combination of clinical features of cerebellar ataxias and spastic paraplegias. Studies of gene expression at the RNA level have been performed in human tissues and different ataxia mouse models These studies concluded to a number of candidate involved biological pathways, including glutamate signaling, calcium signaling, synaptic transmission, DNA repair pathways, cell cycle, metabolic processes, and receptor-mediated signaling pathways [11,12,13,14,15,16,17]. We included additional datasets derived from other tissues, some of which are more accessible to use for future functional investigation or biomarkers discovery This approach would enable us to examine whether differential gene expression and pathway analysis findings in neurons are tissue specific or whether these are represented in additional tissues. Our investigation encourages further exploration of the sphingolipid pathways in relation to SA pathogenesis, in order to conclude to more specific mechanisms that lead to the development of the disease
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