Mutant SOD1 and Mitochondrial Damage Alter Expression and Splicing of Genes Controlling Neuritogenesis in Models of Neurodegeneration

作者：Lenzken Silvia C; Romeo Valentina; Zolezzi Francesca; Cordero Francesca; Lamorte Giuseppe; Bonanno Davide; Biancolini Donatella; Cozzolino Mauro; Pesaresi Maria Grazia; Maracchioni Alessia; Sanges Remo; Achsel Tilmann; Carri Maria Teresa; Calogero Raffaele A; Barabino Silvia M L^*

来源：Human Mutation, 2011, 32(2): 168-182.

DOI：10.1002/humu.21394

• ALS
• axon guidance
• microarray
• mitochondria
• neurodegeneration
• RNA splicing
• SOD1

Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders including Parkinson, Alzheimer, and Amyotrophic Lateral Sclerosis (ALS). In addition, aberrant mRNA splicing has been documented in neurodegeneration. To characterize the cellular response to mitochondrial perturbations at the level of gene expression and alternative pre-mRNA splicing we used splicing-sensitive microarrays to profile human neuroblastoma SH-SY5Y cells treated with paraquat, a neurotoxic herbicide that induces the formation of reactive oxygen species and causes mitochondrial damage in animal models, and SH-SY5Y cells stably expressing the mutant G93A-SOD1 protein, one of the genetic causes of ALS. In both models we identified a common set of genes whose expression and alternative splicing are deregulated. Pathway analysis of the deregulated genes revealed enrichment in genes involved in neuritogenesis, axon growth and guidance, and synaptogenesis. Alterations in transcription and pre-mRNA splicing of candidate genes were confirmed experimentally in the cell line models as well as in brain and spinal cord of transgenic mice carrying the G93A-SOD1 mutation. Our findings expand the realm of the pathways implicated in neurodegeneration and suggest that alterations of axonal function may descend directly from mitochondrial damage. Hum Mutat 32:168-182, 2011.

• 出版日期2011-2