Genome-wide analysis of a reversible neurodegenerative process in Drosophila reveals the regulation of potential neuroprotective genes

Background: Neurodegenerative diseases are progressive, irreversible and affect an increasing proportion of the human population. Among the multiple origins of neurodegeneration are mutations in specific genes. For example, Drosophila mutants for spalt-like (sall) genes exhibit neurodegeneration of the central nervous system at stage 16 of embryonic development, with greatly enlarged extracellular space and deficient cytoskeleton among other features. Surprisingly, this phenotype reverts by embryonic stage 17, suggesting that Drosophila sall mutants have the potential to recover from the neurodegenerative process. Results: We hypothesize that the recovery from the neurodegenerative phenotype in sall mutants is mediated by a reorganization of its transcriptome that counteracts the loss of Sall. To identify genes associated with the reversal of neurodegeneration, we used RNA high throughput sequencing to compare the transcriptome of Drosophila sall mutant and wild type embryos collected at the same stages. Differential expression analysis indicates that a predominant effect of the mutation is the upregulation of putative sall target genes at stages 16 and 17. In addition, the mutation has also a global effect on the number of genes that are regulated during the transition from stage 16 to 17. The functional groups with highest percentage of misregulated genes are the Redox group at stage 16 and the Immune response at stage 17, among others. Conclusions: mRNA-Seq analysis demonstrates that the neurodegenerative phenotype observed at stage 16 in sall mutants is temporally associated with transcriptional changes for 25 genes that were already known to be biological relevant for neurodegeneration as well as for 195 genes non previously associated with neurodegeneration. We also identified transcriptional changes temporally associated with the reversion of this neurodegenerative process in about 480 genes, including 56 genes already demonstrated to be associated with either neurodegeneration or neuroprotection. These genes belong to several functional categories, mainly Neuronal, Neurodegeneration/protection, Immune response, Redox, Salt stress, Tissue regeneration, Starvation and Life span/Aging. Based on the homology of Drosophila and human genes, our study might help to better understand neurodegenerative diseases and unveil genes involved in neuroprotection also in humans.