NEUROTROPHIC FACTORS IN THE PATHOGENESIS OF PSYCHIATRIC AND NEURODEGENERATIVE DISEASES
Psychiatric and neurodegenerative diseases are triggered by a combination of genetic and environmental factors that induce the disconnection of certain neuronal circuits and / or the elimination of neurons altering human behavior. Neurotrophic factors are proteins that promote neuronal survival, differentiation and synaptic plasticity, and therefore alterations in their levels may contribute to the pathogenesis of central nervous system diseases. Some examples of the neurotrophic factors and their receptors that we study in our laboratory include NGF, BDNF, GDNF, SorCS2, Sortilin, SorLa, p75NTR, and TrkB among others. In particular, our group is interested in a genetic variant (polymorphism) present in a high proportion of the world population (approximately 25%) that sensitizes human carriers to develop certain diseases such as post-traumatic stress disorder, depression, anxiety, schizophrenia, additions, Parkinson's disease, Alzheimer's disease and epilepsy. The mechanisms by which this polymorphism increases the incidence of these diseases are unknown and are the main research focus of our research team. This polymorphism induces the substitution of a valine amino acid by a methionine in the middle of the sequence of a peptide called prodomain of BDNF, which is part of a neurotrophic factor. We studied the impact of the prodomain Met variant (associated with the aforementioned diseases) on the cytoskeleton, intracellular protein/membrane trafficking, signaling pathways, and cytoarchitecture of hippocampal and dopaminergic neurons in vitro and in vivo. In addition, we are interested in the impact of alpha-synuclein on the structure and function of dopaminergic neurons. These investigations contribute to understand the cellular and molecular bases of central nervous system diseases development. The experimental approaches utilized in our laboratory include tools of structural biology, biochemistry, cellular and molecular biology, and behavioral studies.
GRANTS
6- PICT-D - Fondo para la Investigación Científica y Tecnológica (FONCyT).
5- Proyectos de Investigación y Desarrollo (PID) - Ministerio de Ciencia y Tecnología de la Provincia de Córdoba.1- Proyectos de Investigación y Desarrollo (PID) - Ministerio de Ciencia y Tecnología de la Provincia de Córdoba.
4- PICT-B - Fondo para la Investigación Científica y Tecnológica (FONCyT).
3- Narsad Young Investigator Grant – Brain and Behavior Foundation.
2- International Brain Research Organization (IBRO) Return Home Fellowship.
1- International Society for Neurochemistry (ISN) Return Home Grant.
ORIGINAL ARTICLES
2020- Jing Wang*, Agustin Anastasia*, Henrietta Bains, Joanna I. Giza, David G. Clossey, Jingjing Deng, Thomas A. Neubert, William J. Rice, Francis S. Lee, Barbara L. Hempstead, Clay Bracken. Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination. Metallomics DOI: 10.1039/d0mt00108b. * Equal contribution.
2018- Joanna I. Giza, Jihye Kim, Heidi C. Meyer, Agustin Anastasia, Iva Dincheva, Crystal I. Zheng, Katherine Lopez, Henrietta Bains, Jianmin Yang, Clay Bracken, Conor Liston, Deqiang Jing, Barbara L. Hempstead, Francis S. Lee. The BDNF Val66Met prodomain disassembles dendritic spines altering fear extinction circuitry and behavior. Neuron 99(6):1356.
2017- Zanin JP, Unsain N, Anastasia A. Growth factors and hormones pro-peptides: the unexpected adventures of the BDNF prodomain. Review in J Neurochemistry 141(3):330-340. May 2017.
2017- Wang J, Bains H, Anastasia A, Bracken C.NMR backbone resonance assignments of the prodomain variants of BDNF in the urea denatured state. Biomol NMR Assign. 2017 Sep 20. doi: 10.1007/s12104-017-9777-0.
2015- Agustín Anastasía*, Philip A. Barker, Moses V. Chao, Barbara L. Hempstead*. “Detection of p75NTR trimers: implications for receptor stoichiometry and activation”. The Journal of Neuroscience 35(34):11911–11920. *= co-corresponding authors.
2015- Bridgin G. Lee, Agustin Anastasia, Barbara L. Hempstead, Francis S. Lee, Julie A. Blendy. “Effects of the BDNF Val66Met Polymorphism on anxiety-like behavior following nicotine withdrawal in mice”. Nicotine & Tobacco Research 17(12):1428-35.
2014- Anastasia A, Deinhardt K, Wang S, Martin L, Nichol D, Irmady K, Trinh J, Parada L, Rafii S, Hempstead BL, Kermani P. “Trkb signaling in pericytes is required for cardiac microvessel stabilization”. PLoS One, 9(1):e87406.
2013- Takeda K, Kermani P, Anastasia A, Obinata Y, Hempstead BL, Kurihara H. “BDNF protects human vascular endothelial cells from TNFα-induced apoptosis”. Biochem Cell Biol. 91(5):341-9.
2013- Anastasia A, Deinhardt K, Chao MV, Will NE, Irmady K, Lee FS, Hempstead BL, Bracken C. “Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction”. Nature Communications, 4:2490.
2012- Kalous A, Nangle MR, Anastasia A, Hempstead BL, Keast JR. “Neurotrophic actions initiated by proNGF in adult sensory neurons may require peri-somatic glia to drive local cleavage to NGF”. Journal of Neurochemistry, 122(3):523-36.
2011- Anastasía A, Wojnacki J, de Erausquin GA, Mascó DH. “Glial cell-line derived neurotrophic factor is essential for electroconvulsive shock-induced neuroprotection in an animal model of Parkinson's disease”. Neuroscience, 195:100–111.
2011- Benítez BA, Belálcazar HM, Anastasía A, Mamah DT, Zorumski CF, Mascó DH, Herrera DG, de Erausquin GA. “Functional reduction of SK3-mediated currents precedes AMPA-receptor-mediated excitotoxicity in dopaminergic neurons”. Neuropharmacology, 60(7-8):1176-86.
2009- Agustín Anastasía, Luciana Torre, Gabriel A. de Erausquin, Daniel H. Mascó. “Enriched Environment Protects the Nigrostriatal Dopaminergic System and Induces Astroglial Reaction in the 6-OHDA rat model of Parkinson’s Disease”. Journal of Neurochemistry, 109:755-765.
2008 - Héctor Alejandro Guidobaldi, María Eugenia Teves, Diego Rafael Uñates, Agustín Anastasía, Laura Cecilia Giojalas. “Progesterone from the cumulus cells is the sperm chemoattractant secreted by the rabbit oocyte cumulus complex”. Plos One 3(8):e3040.
2008- Unsain, Nicolás; Nuñez, Nelson; Anastasía, Agustín, and Mascó, Daniel H. “Status Epilepticus induces a TrkB to p75 Neurotrophin receptor switch and increases brain-derived neurotrophic factor interaction with p75 Neurotrophin Receptor: an initial event in neuronal injury induction”. Neuroscience 154:978-993.
2007- Agustín Anastasía, Gabriel A. De Erausquin, José Wojnacki, & Daniel. H. Mascó. Neuroprotection of Dopaminergic Neurons by Electroconvulsive Shock in an Animal Model of Parkinson’s Disease. Journal of Neurochemistry 103(4):1542-52.
OTHER PUBLICATIONS
2017- Zanin JP, Unsain N, Anastasia A. Growth factors and hormones pro-peptides: the unexpected adventures of the BDNF prodomain. Review in J Neurochemistry 141(3):330-340. May 2017.
2015- Margarita Arango-Lievano, Agustin Anastasia, Freddy Jeanneteau. Book Chapter: ProBDNF Biology and Emerging Roles in the CNS: The Unexpected Journey of Proneurotrophins. Nova Science Publishers. ISBN: 978-1-63483-799-6.
2014- Agustín Anastasía and Barbara L. Hempstead. “BDNF function in health and disease”. Poster in Nature Review Neuroscience, 15(2).