Objective:

To determine the mechanism underlying cell-type specific alpha-synuclein-induced transcriptional programs 

Background:

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by motor, autonomic, and cerebellar dysfunction. In contrast with other alpha-synucleinopathies, MSA features alpha-synuclein aggregates predominantly in oligodendrocytes, rather than neurons. We developed a Drosophila model for studying the differing effects of alpha-synuclein in glia versus neurons. In previous studies, we identified differential gene expression between glial and neuronal alpha-synuclein using bulk RNAseq. 

Design/Methods:

We performed motif enrichment analysis on differentially expressed genes in neurons or glia using Hypergeometric Optimization of Motif EnRichment (HOMER). We used gene ontology to identity biological pathways regulated by transcription factors. Specific genes were validated using quantitative real-time PCR and immunohistochemistry.  

Results:

We identified several motifs that were significantly enriched in differentially expressed genes. One such motif was for the transcription factor caudal (cad), a Drosophila ortholog of caudal type homeobox 2 (CDX2). cad itself as well as many genes with cad motifs were upregulated with glial alpha-synuclein. Gene ontology analysis demonstrated that many of these genes are involved in proteolysis. 

Conclusions:

Here we identify the transcription factor caudal as one mediator of a glial alpha-synuclein induced transcriptional program involving an upregulation of proteolysis. More broadly, this work illustrates how our Drosophila model may be used for mechanistic investigation of cell-type specific alpha-synuclein-induced gene regulation.