Dysregulated expression and alternative splicing of genes controlling neuritogenesis and axon guidance revealed by exon-sensitive microarrays in models of neurodegeneration

Mitochondrial dysfunction has been directly or indirectly implicated in the pathogenesis of a number of neurodegenerative disorders including Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS). We used exon-sentive microarrays to characterize the responses to different mitochondrial perturbations in cellular models. We examined human SH-SY5Y neuroblastoma cells treated with paraquat, a neurotoxic herbicide which both catalyzes the formation of reactive oxygen species (ROS) and induces mitochondrial damage in animal models, and SH-SY5Y cells stably expressing the mutant SOD1(G93A) protein, one of the genetic causes of ALS. We identified a common set of genes that have a deregulated transcription and alternative splicing in both models. Noticeably, pathway analysis revealed that the expression of a subset of genes involved in neuritogenesis and axon guidance is perturbed, suggesting that alterations of axonal function may descend directly from mitochondrial damage and be responsible for neurodegenerative conditions.

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Lenzken SC, Romeo V, Zolezzi F, Cordero F, Lamorte G, Bonanno D, Biancolini D, Cozzolino M, Pesaresi MG, Maracchioni A, Sanges R, Achsel T, Carrì MT, Calogero RA, Barabino SM