Abstract
GSK3 (glycogen synthase kinase 3) is a conserved protein kinase governing numerous regulatory pathways. In Drosophila melanogaster, GSK3 is encoded by shaggy (sgg), which forms 17 annotated transcripts corresponding to 10 protein isoforms. Our goal was to demonstrate how differential sgg transcription affects lifespan, which GSK3 isoforms are important for the nervous system, and which changes in the nervous system accompany accelerated aging. Overexpression of three sgg transcripts affected the lifespan in a stage- and tissue-specific way: sgg-RA and sgg-RO affected the lifespan only when overexpressed in muscles and in embryos, respectively; the essential sgg-RB transcript affected lifespan when overexpressed in all tissues tested. In the nervous system, only sgg-RB overexpression affected lifespan, causing accelerated aging in a neuron-specific way, with the strongest effects in dopaminergic neurons and the weakest effects in GABAergic neurons. Pan-neuronal sgg-RB overexpression violated the properties of the nervous system, including the integrity of neuron bodies; the number, distribution, and structure of mitochondria; cytoskeletal characteristics; and synaptic activity. Such changes observed in young individuals indicated premature aging of their nervous system, which paralleled a decline in survival. Our findings demonstrated the key role of GSK3 in ensuring the link between the pathology of neurons and lifespan.
Highlights
GSK3 is an actively studied, highly conserved serine–threonine protein kinase that is primarily regulated by inhibition and is involved in multiple signaling pathways that regulate embryogenesis and differentiation; cell renewal, migration, and apoptosis; gene transcription; metabolism; and survival via more than 50 target proteins with phosphorylation sites for GSK3 [1,2]
We suggest that the lifespan reduction caused by aberrations in GSK3 expression in the nervous system is based on pathological changes in neurons
Understanding the genetic and molecular basis of pathological changes of the nervous system underlying accelerated aging and shortening of lifespan are important for the development of evidence-based recommendations for life extension
Summary
GSK3 (glycogen synthase kinase 3) is an actively studied, highly conserved serine–threonine protein kinase that is primarily regulated by inhibition and is involved in multiple signaling pathways that regulate embryogenesis and differentiation; cell renewal, migration, and apoptosis; gene transcription; metabolism; and survival via more than 50 target proteins with phosphorylation sites for GSK3 [1,2]. In D. melanogaster, GSK3 plays multiple roles in the development and function of the nervous system, starting from the early development stages. GSK3 directly phosphorylates aPKC (atypical protein kinase C) [3,4], a key component ensuring asymmetric neuroblast division during D. melanogaster early development. GSK3 controls synapse formation, growth, and morphological structure by controlling the dynamics of the microtubule cytoskeleton [7,8,9] and regulates axonal stability and neural circuit integrity via the Wnt pathway [10]. GSK3 directly phosphorylates microtubule-associated protein tau [11,12]. Overexpression of human tau in D. melanogaster disrupts axonal transport causing vesicle aggregation, and co-overexpression of constitutively active GSK3 enhances the effects [13]. Two functions of GSK3 attracted our attention to this protein
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