Comparative analysis of TFEB overexpression in Parkinson's disease-relevant cell types Anne C. Campbell1, Catherine L. Nezich1, Joost Groot1, Warren D. Hirst1 Research & Early Development, Biogen, Cambridge, MA, USA
Significant evidence supports a crucial role for the autophagy-lysosomal pathway in the degradation of misfolded proteins that accumulate in numerous neurodegenerative disorders, including Parkinson's disease (PD). Lysosomes and autophagosomes, the two major degradative components of this pathway, are believed to be, in part, regulated by the action of the transcription factor EB (TFEB). TFEB is normally sequestered inactive in the cytosol but accumulates in the nucleus upon activation by various cellular and lysosomal stresses where it binds to a 10bp CLEAR (Coordinated Lysosomal Expression and Regulation) promoter motif and upregulates the transcription of numerous lysosomal and autophagy genes. Although hundreds of TFEB target genes have been identified, previous transcriptome profiling efforts have largely been carried out in immortalized cell lines rather than in disease-relevant CNS cell types. The purpose of the present study was to therefore conduct a comparative analysis of cell type-specific transcript response following TFEB overexpression in these CNS-relevant cell types. Using RNA sequencing we have evaluated the expression profiles of human iPSC-derived astrocytes and dopaminergic neurons, as well as a HeLa cell reference line following TFEB overexpression. We have identified >1500 differentially expressed genes (p adjusted < 0.05, HeLa), most of which have not yet been reported as TFEB targets. A preliminary mRNA profiling analysis showed a 27% overlap between significantly upregulated genes in both HeLa and one CNS cell type. We have also identified many differentially enriched pathways associated with TFEB overexpression using a highly sophisticated gene set analysis approach. Significant pathways identified include the expected upregulation of autophagy, as well as a variety of neurophysiological processes. Such an analysis provides increased confidence in the strategy of targeting TFEB activation as a novel therapeutic intervention to treat diseases associated with autophagy and lysosomal dysfunction, like PD, as well as clearly identify the effect of TFEB on the major CNS cell types.
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