Integrated Computational Analysis Highlights unique miRNA Signatures in the Subventricular Zone and Striatum of GM2 Gangliosidosis Animal Models

Abstract

This work explores for the first time the potential contribution of microRNAs (miRNAs) to the pathophysiology of the GM2 gangliosidosis, a group of Lysosomal Storage Diseases. In spite of the genetic origin of GM2 gangliosidosis, the cascade of events leading from the gene/protein defects to the cell dysfunction and death is not fully elucidated. At present, there is no cure for patients. Taking advantage of the animal models of two forms of GM2 gangliosidosis, Tay-Sachs (TSD) and Sandhoff (SD) diseases, we performed a microRNA screening in the brain subventricular zone (SVZ) and striatum (STR), which feature the neurogenesis and neurodegeneration states, respectively, in adult mutant mice. We found abnormal expression of a panel of miRNAs involved in lipid metabolism, CNS development and homeostasis, and neuropathological processes, highlighting region- and disease-specific profiles of miRNA expression. Moreover, by using a computational analysis approach, we identified a unique disease- (SD or TSD) and brain region-specific (SVZ vs. STR) miRNAs signatures of predicted networks potentially related to the pathogenesis of the diseases. These results may contribute to the understanding of GM2 gangliosidosis pathophysiology, with the aim of developing effective treatments.

The Role of the miR-17-92 Cluster in Autophagy and Atherosclerosis Supports Its Link to Lysosomal Storage Diseases

“…Other LSDs also present alterations in miRNAs from the miR-17-92 family. This is the case for GM2-Gangliosidosis deficiencies, such as Tay-Sachs and Sandho diseases, in which a panel of nine miRNAs that included miR-19a have been identified as highly downregulated [105].…”

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

“…For example, cholesterol accumulates in late endosomes and lysosomes in the juvenile form of Niemann Pick type C disease characterized by progressive neurodegeneration similar to AD, including NFTs formation and increased APP amyloidogenic processing [ 206 , 303 , 304 ]. An extensive study reported APP-CTFs, Aβ peptide, and α-Synuclein accumulation in the Sandhoff mouse model [ 305 , 306 , 307 ] and ganglioside-bound Aβ-peptide in post-mortem human brains of patients with GM1 gangliosidosis and GM2 gangliosidosis [ 308 ]. Other evidence came from the presence of soluble Aβ(1-40)-peptide in post-mortem brains of patients with Mucopolysaccharidosis type 1 [ 309 ], in the mouse models of Mucopolysaccharidosis type IIIB [ 310 ], and the neuropathic form of Gaucher disease [ 311 ].…”