Abstract Details

Title Caudal Mediates a Glial Alpha-synuclein Induced Increase in Proteolysis-Related Genes

Topic Movement Disorders

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 5-015

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.

Authors/Disclosures
Ming Shen, Other PRESENTER	Ms. Shen has nothing to disclose.
Abby L. Olsen, MD (University of Pittsburgh)	An immediate family member of Dr. Olsen has received personal compensation for serving as an employee of Rheos Medicines. An immediate family member of Dr. Olsen has received personal compensation for serving as an employee of Novasenta. An immediate family member of Dr. Olsen has received personal compensation for serving as an employee of Biohaven. The institution of Dr. Olsen has received research support from NINDS. The institution of Dr. Olsen has received research support from DoD. The institution of Dr. Olsen has received research support from American Parkinson's Disease Association. The institution of Dr. Olsen has received research support from Alzheimer's Association.

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