Although ALS shows symptoms in motor neurons, the function of non-neuronal cells is also affected by and affecting to disease pathogenesis especially when ALS is genetically inherited. To quickly find the genetic components that are closely associated with onset or pathogenesis of ALS, a simple genetic model system is suitable for that task. However, there is few genetic model system that can be used to study the non-neuronal cell-mediated ALS. The powerful genetic tools available in the fly system can help to uncover molecular mechanisms underlying non-neuronal cell-mediated ALS. Those tools allow us to perform spatial and temporal genetic manipulation in ultrafine resolution to distinguish the role of C9ORF72 in specific subtype of glia from neuron. In this proposal, we will take advantage of using well-established C9ORF72 mutant strains available in the fly system. It is well-known that the mutation of the human gene, C9ORF72 explains the most of genetic causes for both ALS and FTD. We recently found that expression of C9ORF72 dipeptides in a small subset of glial cell population affect the interaction between glia and neuron. Those animals show developmental defect when the expression level of toxic dipeptide is high, however, show neurodegenerative phenotype comparable to human motor neuron symptom when expression is delayed until late adult stage.
We have three objectives:
1) We will test the effect of glial cells on ALS/FTD pathogenesis.
2) We will establish the glia-mediated C9ORF72 disease pathogenesis model.
3) We will perform suppressor screening for C9ORF72-mediated glial toxicity.
This study will uncover how C9ORF72 expression in a small subset of a glial cell population can affect the glia-neuron interaction then cause the ALS-like symptoms. It will help to understand the mechanisms of glial cell-mediated ALS symptoms and to find the genetic components that are involved in ALS pathogenesis.
