Transcriptional regulator of DR responsive genes extends lifespan and regulate Tau pathology in Drosophila
Authors: Sudipta Bar; Patrick Wai-Lun Li; Tyler Hilsabeck; Guiping Du; Simon Melov; Pankaj Kapahi
Affiliation: Buck Institute for research on aging
Keywords: i. lifespan; a. neural degeneration
Dietary restriction (DR) is a robust intervention that slows aging in multiple species and staves off age-related diseases, including Alzheimer’s disease and related dementias (ADRDs). Despite identifying some of the genetic risk factors for Alzheimer's disease (AD), therapeutics to treat ADRDs have been unsuccessful. However, the underlying mechanisms by which DR protects against AD are unknown. Identifying the mechanism behind the DR-mediated neuroprotection and lifespan extension can lead us to new therapeutic targets for AD. Using Translating Ribosome affinity purification (TRAP) method we have identified tissue-specific gene expression profiles of Drosophila in Ad libitum (AL) and DR conditions. We have identified a relatively large proportion of the unique DR-responsive genes to be altered in neurons. Utilizing bioinformatics approaches and publicly available chromatin immunoprecipitation sequencing (ChIP-seq) data from the ENCODE consortium we identified transcription factors (TFs) that are significantly enriched at promoter regions of genes that are upregulated or downregulated in fly brains on DR, compared to flies reared on AL diet. Screening of those TFs in lifespan extension revealed downregulation of Jarid2 extends lifespan and rescues tau pathology in a fly model of AD. We determined there are 359 downstream target genes of Jarid2 among which homolog of 16 genes have been reported to influence AD risk. Gene ontology (GO) enrichment analysis of the Jarid2 downstream targets identified enrichment of several biological processes including system development, nervous system development, neurogenesis, axon development, etc. We identified the downregulation of a neurogenesis factor NetB, a downstream target of Jarid2, which abrogates the DR effect. Hence we are working to understand the role of Jarid2 and NetB in neuroprotection to establish as potential targets for AD.