Regulation of Social Stress and Neural Degeneration by Activity-Regulated Genes and Epigenetic Mechanisms in Dopaminergi
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Regulation of Social Stress and Neural Degeneration by Activity-Regulated Genes and Epigenetic Mechanisms in Dopaminergic Neurons Clement Kent 1
&
Pavan Agrawal 2
Received: 19 May 2020 / Accepted: 22 July 2020 # The Author(s) 2020
Abstract Transcriptional and epigenetic regulation of both dopaminergic neurons and their accompanying glial cells is of great interest in the search for therapies for neurodegenerative disorders such as Parkinson’s disease (PD). In this review, we collate transcriptional and epigenetic changes identified in adult Drosophila melanogaster dopaminergic neurons in response to either prolonged social deprivation or social enrichment, and compare them with changes identified in mammalian dopaminergic neurons during normal development, stress, injury, and neurodegeneration. Surprisingly, a small set of activity-regulated genes (ARG) encoding transcription factors, and a specific pattern of epigenetic marks on gene promoters, are conserved in dopaminergic neurons over the long evolutionary period between mammals and insects. In addition to their classical function as immediate early genes to mark acute neuronal activity, these ARG transcription factors are repurposed in both insects and mammals to respond to chronic perturbations such as social enrichment, social stress, nerve injury, and neurodegeneration. We suggest that these ARG transcription factors and epigenetic marks may represent important targets for future therapeutic intervention strategies in various neurodegenerative disorders including PD. Keywords Dopamine . Activity-regulated genes . Immediate early genes . Parkinson’s disease . Social isolation . Drosophila melanogaster
Introduction Neurons and glia can enter into, stay in, and exit from epigenetically regulated semi-stable states. Cell fate choice during normal neuronal development is a one-way journey through pro-neural states to a stable, differentiated mature neuron. However, after injury, several states may be maintained for long periods, possibly followed by a reversal to a normal mature neural state [1]. Not all neural state changes are related to disease, injury, or development; for example, changes in environmental conditions and exposure to stressors may cause * Pavan Agrawal [email protected] Clement Kent [email protected] 1
Department of Biology, York University, Toronto, ON M3J 1P3, Canada
2
Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
groups of neurons to become more or less active for prolonged periods. A well-studied example of this is the effect of prenatal and early life stress, which produces epigenetic modifications in neural genes resulting in persistent behavioral changes [2–4]. We studied epigenetic and transcriptional changes in dopaminergic neurons (DANs) in the fruit fly Drosophila melanogaster, where prolonged social isolation and social enrichment cause restructuring of the epigenetic landscape [5]. DANs are involved in neuronal differentiation [6]
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