Ttiis research focuses on the molecular mechanisms of neuromodulation. Neuromodulators are typically neuropeptides, or monoamines such as dopamine, noradrenaline, and serotonin. Defects in neuromodulatory pathways do not usually lead to death, but can cause mental disorders such as autism, depression, schizophrenia, and attention deficit and hyperactivity disorder, as well as eating disorders and drug addiction. Neuromodulators are released from dense-core vesicles (DCVs). Little is known about DCV biogenesis, transport, and release, in part because it has not been possible to biochemically purify proteins specific to DCVs as it has for synaptic vesicles. Instead, a genetic screen in the nematode C. elegans was performed and successfully identified a set of novel molecules that act in a dense-core vesicle trafficking pathway. These include the small GTPase RAB-2 and two novel effectors, RUND-1 and CCCP-1. These molecules physically interact and are colocalized at the trans-Golgi network where DCVs are generated. Loss of these molecules leads to defects in sorting DCV cargos. This proposal aims to identify additional molecules acting In DCV trafficking and determine their mechanism of action.
Aim 3 will identify more molecules acting in the RAB-2 pathway using genetic and biochemical screens. These new molecules will be characterized for their effects on DCV trafficking, their physical and genetic interactions with known molecules, and their cellular localization.'Using similar methods.
Aim 4 will identify and characterize new molecules acting in a pathway with HID-1, in parallel to the RAB-2 pathway to regulate DCV trafficking. This research directly relates to the mission of NIMH, in particular to the first objective of the NIMH Strategic Plan: to investigate the causes of mental disorders. Mental illness can be caused either by too little or too much of certain neuromodulators. Thus, a better understanding ofthe mechanisms by which neuromodulators are released could lead to the development of drugs that either increase or reduce release, to compensate for the defect. In particular, molecules such as the ones I have identified that are necessary for release would be good targets for drugs to treat disorders due to too much release. Additionally, as dense-core vesicle pathways are modulatory rather than essential for neurotransmission, humans with mutations in these pathways would be expected to be viable, but mentally ill. Thus, the new genes identified in my work are good candidates for genes linked to mental health disease in humans.
Human nervous system disorders such as autism, schizophrenia, depression and attention deficit/ hyperactivity disorder are linked to abnormal levels of brain chemicals that affect the strength of signaling between different brain cells. This proposal aims to understand how such chemicals are released in the nervous system so that better drugs can be designed to treat these disorders.
|Coleman, Brantley; Topalidou, Irini; Ailion, Michael (2018) Modulation of Gq-Rho Signaling by the ERK MAPK Pathway Controls Locomotion in Caenorhabditis elegans. Genetics 209:523-535|
|Topalidou, Irini; Chen, Pin-An; Cooper, Kirsten et al. (2017) The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans. Genetics 206:265-282|
|Hoyt, Jill M; Wilson, Samuel K; Kasa, Madhuri et al. (2017) The SEK-1 p38 MAP Kinase Pathway Modulates Gq Signaling in Caenorhabditis elegans. G3 (Bethesda) 7:2979-2989|
|Cattin-Ortolá, Jérôme; Topalidou, Irini; Dosey, Annie et al. (2017) The dense-core vesicle maturation protein CCCP-1 binds RAB-2 and membranes through its C-terminal domain. Traffic 18:720-732|
|Topalidou, Irini; Cattin-Ortolá, Jérôme; Pappas, Andrea L et al. (2016) The EARP Complex and Its Interactor EIPR-1 Are Required for Cargo Sorting to Dense-Core Vesicles. PLoS Genet 12:e1006074|
|Ailion, Michael; Hannemann, Mandy; Dalton, Susan et al. (2014) Two Rab2 interactors regulate dense-core vesicle maturation. Neuron 82:167-80|
|Frøkjær-Jensen, Christian; Davis, M Wayne; Ailion, Michael et al. (2012) Improved Mos1-mediated transgenesis in C. elegans. Nat Methods 9:117-8|
|Luo, L; Hannemann, M; Koenig, S et al. (2011) The Caenorhabditis elegans GARP complex contains the conserved Vps51 subunit and is required to maintain lysosomal morphology. Mol Biol Cell 22:2564-78|