Heather Skye Comstra

Bio: Heather Skye Comstra is an academic researcher from Emory University. The author has contributed to research in topics: Menkes disease & ATP7A. The author has an hindex of 5, co-authored 8 publications receiving 163 citations.

The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors

Abstract: People need a source of copper in their diet because this nutrient is used to produce the pigment in hair and skin, the connective tissue in tendons and ligaments, and some of the small molecules that allow brain cells to communicate. There is an ideal range of copper that allows cells to carry out these processes. Both too much and too little copper can have negative effects on health, particularly related to how the brain works. Cells contain multiple proteins that bind to copper and transport it wherever it is needed. People with mutations that mean they lack one of these copper transporters, ATP7A, often have serious damage to their nervous system that cannot be explained by the current understanding of how this protein works. Comstra et al. set out to establish a comprehensive list of proteins that interact with ATP7A to better understand how this transporter works and how it is regulated. The search revealed that ATP7A interacts with hundreds of proteins present in different compartments within cells, many of which had not previously been associated with balancing copper levels in cells and the body. Like ATP7A, many of these proteins (or the protein complexes that contain them) are known to affect nerves and brain activity when they are mutated. Next, Comstra et al. engineered human cells grown in the laboratory to lack one of the protein complexes that interacts with ATP7A, the COG complex. Cells without this protein complex had 50% less ATP7A than normal human cells and very low levels of copper too. These mutant cells also had problems generating the energy that they need, because the structures in cells that provide them with energy – the mitochondria – were impaired; adding copper to the cells improved the activity of their mitochondria. Mutations in the COG complex cause the brain to develop abnormally, and the finding that deleting the COG complex from cells causes copper deficiency now helps to explain why. Further characterization of the proteins that interact with ATP7A and the COG complex will contribute to our understanding of how cells regulate copper and how copper levels affect the brain.

Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor

Abstract: Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. Although few genes and environmental factors have been linked, the intervening cellular and molecular mechanisms connecting a disorder susceptibility gene with environmental factors remain mostly unexplored. Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. Mutations in ATP7A result in Menkes disease, a disorder of copper metabolism. Dysbindin/BLOC-1 and ATP7A genetically and biochemically interact. Furthermore, disruption of this pathway causes alteration in the transcriptional profile of copper-regulatory and dependent factors in the hippocampus of dysbindin/BLOC-1-null mice. Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency.

Presynaptic membrane retrieval and endosome biology: defining molecularly heterogeneous synaptic vesicles.

Abstract: The release and uptake of neurotransmitters by synaptic vesicles is a tightly controlled process that occurs in response to diverse stimuli at morphologically disparate synapses. To meet these architectural and functional synaptic demands, it follows that there should be diversity in the mechanisms that control their secretion and retrieval and possibly in the composition of synaptic vesicles within the same terminal. Here we pay particular attention to areas where such diversity is generated, such as the variance in exocytosis/endocytosis coupling, SNAREs defining functionally diverse synaptic vesicle populations and the adaptor-dependent sorting machineries capable of generating vesicle diversity. We argue that there are various synaptic vesicle recycling pathways at any given synapse and discuss several lines of evidence that support the role of the endosome in synaptic vesicle recycling.

Endocytosis, Signaling, and Beyond

Abstract: The endocytic network comprises a vast and intricate system of membrane-delimited cell entry and cargo sorting routes running between biochemically and functionally distinct intracellular compartments. The endocytic network caters to the organization and redistribution of diverse subcellular components, and mediates appropriate shuttling and processing of materials acquired from neighboring cells or the extracellular milieu. Such trafficking logistics, despite their importance, represent only one facet of endocytic function. The endocytic network also plays a key role in organizing, mediating, and regulating cellular signal transduction events. Conversely, cellular signaling processes tightly control the endocytic pathway at different steps. The present article provides a perspective on the intimate relationships that exist between particular endocytic and cellular signaling processes in mammalian cells, within the context of understanding the impact of this nexus on integrated physiology.

The road to lysosome-related organelles: Insights from Hermansky-Pudlak syndrome and other rare diseases

Abstract: Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.

Towards a molecular understanding of endosomal trafficking by Retromer and Retriever

Abstract: Endosomes are dynamic intracellular compartments that control the sorting of a constant stream of different transmembrane cargos either for ESCRT-mediated degradation or for egress and recycling to compartments such as the Golgi and the plasma membrane. The recycling of cargos occurs within tubulovesicular membrane domains and is facilitated by peripheral membrane protein machineries that control both membrane remodelling and selection of specific transmembrane cargos. One of the primary sorting machineries is the Retromer complex, which controls the recycling of a large array of different cargo molecules in cooperation with various sorting nexin (SNX) adaptor proteins. Recently a Retromer-like complex was also identified that controls plasma membrane recycling of cargos including integrins and lipoprotein receptors. Termed "Retriever," this complex uses a different SNX family member SNX17 for cargo recognition, and cooperates with the COMMD/CCDC93/CCDC22 (CCC) complex to form a larger assembly called "Commander" to mediate endosomal trafficking. In this review we focus on recent advances that have begun to provide a molecular understanding of these two distantly related transport machineries.

The Synaptic Vesicle Cycle Revisited: New Insights into the Modes and Mechanisms.

Abstract: Neurotransmission is sustained by endocytosis and refilling of synaptic vesicles (SVs) locally within the presynapse. Until recently, a consensus formed that after exocytosis, SVs are recovered by either fusion pore closure (kiss-and-run) or clathrin-mediated endocytosis directly from the plasma membrane. However, recent data have revealed that SV formation is more complex than previously envisaged. For example, two additional recycling pathways have been discovered, ultrafast endocytosis and activity-dependent bulk endocytosis, in which SVs are regenerated from the internalized membrane and synaptic endosomes. Furthermore, these diverse modes of endocytosis appear to influence both the molecular composition and subsequent physiological role of individual SVs. In addition, previously unknown complexity in SV refilling and reclustering has been revealed. This review presents a modern view of the SV life cycle and discusses how neuronal subtype, physiological temperature, and individual activity patterns can recruit different endocytic modes to generate new SVs and sculpt subsequent presynaptic performance.