RNA-Sequencing Uncovers New Genes Involved in ALS Neurodegeneration

In a new study entitled “Transcriptome profiling of expression changes during neuronal death by RNA-Seq,” a research team employed RNA-sequencing to identify novel genes that might help regulate the death of neurons, a characteristic of neurodegenerative diseases. The study was published in the journal Experimental Biology and Medicine.

Vertebrate development of the nervous system requires the death of approximately half the neurons produced in order to create a matching network between neurons and their targets. Notably, however, while this phenotype is required for the correct development of the nervous system, the posterior loss of neurons is characteristic of several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Researchers have posited that, although different in their triggering input, the pathways that lead to neurons’ death during development are likely to share common features with those of neurodegenerative diseases. This assumption suggests that key common genes may underline apoptosis in both development and disease settings, and identifying these genes would increase our understanding of potential therapeutic interventions in degenerative brain disorders.

Here, a research team at Southern Methodist University led by Professor and Chair of Biological Sciences Santosh D’Mello performed RNA-sequencing to identify, in a detailed and comprehensive analysis, genes involved in neuron death. They used as a model a well-established culture of cerebellar granule neurons (CGNs) that were inserted into a medium with low non-depolarizing levels of potassium (LK) to undergo apoptosis (programmed cell death). While previous studies used DNA microarrays to identify genes involved in neuronal death, RNA sequencing is a more robust and in depth-analysis, allowing the researchers to identify unknown transcripts, as well as those whose expression is so low that is not detected by microarrays.

In agreement with its enhanced coverage, here the authors identified 4,334 genes whose expression was significantly altered in LK-treated CGNs – they found the expression of 2,199 genes was up-regulated while 2135 were down-regulated. On the contrary, DNA microarrays detected only several hundred genes as differentially expressed. The genes with altered expression were involved in regulation of cell death and cell survival, as well as cell growth and proliferation. When analyzing for the pathways altered in LK-treated CGNs, the authors identified several pathways, including those involved in mitochondrial dysfunction and oxidative phosphorylation, both previously established as not-working properly in neurodegenerative disorders.

The study identified new genes whose expression profile changes with neuronal death. Further studies will underscore their relevance to neuronal death in neurodegenerative diseases, as noted in a press release by Dr. D’Mello: “This is a first step in the identification of novel but important players regulating neuronal survival and death. Future studies will determine to what extent the novel genes identified in our study are involved in regulating neuronal death, including death associated with neurodegenerative disease.”