Back to Search
Start Over
Mef2 and Gga Interaction in the Brain Modulates Systemic Lifespan
- Publication Year :
- 2023
-
Abstract
- In the past decades several genes and pathways that regulate lifespan were discovered. These genes have a great potential to fundamentally change our understanding of aging and neurodegeneration. In many cases, they were identified as mutations that extend lifespan in a species. However, different species live from few days to several decades and the genes and mechanisms that determine this variation are still unclear. It is also unknown if genes that regulate species-specific lifespan act additively or if they interact in way that greatly change lifespan. Finally, in many species, females live longer than males but the mechanisms behind these differences remain poorly understood. To address these fundamental questions, we selected two Drosophila species with different lifespans, Drosophila melanogaster and Drosophila simulans. These species separated approximately 5.4 Mya and have fixed different pairs of alleles that have been co-evolving. If co-evolving pairs of genes determine lifespan, then bringing these different pairs together in a single interspecific hybrid organism should cause a dysregulation of lifespan. Alternatively, if the contribution of genes is additive, then interspecific hybrids should have an intermediate lifespan between each species. We show that D. melanogaster/D. simulans hybrids have severely dysregulated lifespans with extremely long-lived males and very short-lived females. This result shows that the lifespans of these species are regulated by interactions between X-linked and autosomal genes compromised by their allelic divergence. To identify these pairs of genes, we searched for divergent X-linked and autosomal genes that physically interact. This search led to the identification of Golgi-localized, gamma-ear-containing, ADP ribosylation factor-binding protein (Gga) and Myocyte enhancer factor 2 (Mef2). Here we show that lifespan depends on an interaction between MEF2 and GGA which adjusts their levels during aging in neurons that project into the mushroom body, a learning and memory center of the brain. Furthermore, we show that GGA levels are stabilized by Heat shock protein 68 (HSP68), which is more strongly expressed in females than males. We propose a model of a “lifespan clock” in which the precise levels and decay rates of MEF2 and GGA determine lifespan.
Details
- Language :
- English
- Database :
- OpenDissertations
- Publication Type :
- Dissertation/ Thesis
- Accession number :
- ddu.oai.etd.ohiolink.edu.case1686656599749076