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Protein monoaminylation in brain: novel mechanisms of neural development, plasticity and disease

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Ian Maze Assistant Professor of Neuroscience and Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai
09 April 2019 from 3:30 PM to 4:30 PM
8 Mueller Lab
Dept of Biology
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Abstract: Persistent changes in neuronal gene expression and synaptic plasticity promote physiological alterations implicated in a wide variety of human developmental and adult neurological disorders. More recently, cell-type and brain region specific epigenetic mechanisms have also been demonstrated to regulate transcriptional programs contributing to neurological disease; however, our understanding of how these mechanisms mediate life-long alterations in neuronal plasticity remains limited. Monoaminergic neurotransmission in the central nervous system plays a critical role in brain development and function, with alterations in monoamine production being implicated in both the development and treatment of numerous neurological diseases including substance abuse disorders, mood syndromes (e.g., major depressive disorder) and neurodegenerative disease (e.g., Parkinson’s disease). Although packaging of monoamines by the vesicular monoamine transporter is essential for numerous aspects of motor function, affect and reward, recent data have demonstrated the additional presence of non-vesicularized pools of monoamines in the nucleus and soma of monoamine producing neurons. Serotonin, as well as other hydrophobic monoamines, has previously been shown to form covalent bonds with specific cytoplasmic/membrane associated proteins catalyzed by the tissue Transglutaminase 2 enzyme. We recently identified histone proteins as robust substrates for monoaminylation in brain. Our data indicate that histone H3 monoaminylations act to alter the binding of adjacent histone/DNA modification interacting proteins (‘readers’) and play a direct and critical role in monoaminergic neuronal transcription. Furthermore, our data demonstrate associations between altered levels of H3 monoaminylations (and the enzymes mediating these marks) and behavioral deficits observed in numerous rodent models of psychiatric illness (e.g., cocaine self-administration, chronic social defeat stress induced ‘depression,’ etc.). Taken together, our data suggest that monoaminergic dysfunction in brain may result in altered genomic enrichment of H3 monoaminylation states (which vary based upon disease state, brain region, cell-type, etc.), thereby potentiating aberrant transcriptional plasticity and the precipitation of neurological impairments. Using a unique combination of chromatin biochemistry, chemical biology, genome-wide and neurobiological approaches, we are fully characterizing the functions of these different protein monoaminylation states, and well as synaptic protein monoaminylations (non-histone substrates), in the contexts of normal neuronal function, as well as in etiologically valid rodent models of human disease; understanding the function of these highly novel molecular phenomena in brain promises to provide transformative insights into the underlying mechanisms of monoamine related brain disorders, and aims to identify novel targets for the development of more effective therapeutics.