Research Faculty

630 West 168th Street
P&S 15-401
New York, NY 10032

Phone: 212-305-6371
Fax: 212-305-5498
Education and Training
1997-2002 B.Sc. Biochemistry. Miguel Hernandez University, Spain
2000-2002 M.S. Biotechnology. Miguel Hernandez University, Spain
2003-2008 Ph.D. Molecular Biology. Autonomous University of Madrid, Spain

Taub Institute

Internal collaborations: Karen Duff, Jonathan A. Javitch, Giuseppe Tosto
Ismael Santa-Maria Perez, Ph.D.
Assistant Professor of Pathology and Cell Biology
Research Summary

Research in our laboratory is focused on understanding the mechanisms maintaining or altering tau proteostasis in neurons, and their relevance in aging and Alzheimer's disease (AD). Intracellular accumulation of neurofibrillary tangles of hyperphosphorylated misfolded tau proteins is one of the main hallmarks in many neurodegenerative diseases, including AD. Little is known about the mechanisms underlying tau dysfunction and neurofibrillary degeneration but a dysfunctional regulation of protein expression has been proposed to participate in the pathogenesis of AD and related tauopathies. In addition, it is unclear whether disturbances in the levels of microRNAs or other molecules that directly regulate tau proteostasis contribute to the pathogenesis of AD. Hence, investigating how certain microRNAs impact tau synthesis, hyperphosphorylation and accumulation in the disease is currently the main interest of our laboratory. In our research, we employ a variety of biochemical, cell culture, transgenic animal (Drosophila and mice) and molecular biology techniques to approach all these questions.
Selected Publications

Santa-Maria I., Alaniz M.E., Renwick N., Cela C., Fulga T.A., Van Vactor D., Tuschl T., Clark L.N., Shelanski M.L., McCabe B.D., Crary J.F. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. Journal of Clinical Investigation. 2015; 125(2): 681-686

Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL 3rd, Wisniewski T, Woltjer RL, Yamada M, Nelson PT. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014;128(6):755-66

Santa-Maria I., Haggiagi A., Liu X., Wasserscheid J., Nelson PT., Dewar K., Clark LN., Crary JF. The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathologica. 2012; 124(5): 693-704

Santa-Maria I., Varghese M., Ksiezak-Reding H., Dzhun A., Wang J., Pasinetti GM. Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes. Journal of Biological Chemistry. 2012; 287(24): 20522-33

Santa-Maria I., Diaz-Ruiz C., Ksiezak-Reding H., Cheng A., Ho L., Wang J., Pasinetti G.M. GSPE interferes with tau aggregation in vivo: implication for treating tauopathy. Neurobiology of Aging. 2012; 33(9): 2072-81

Ksiezak-Reding H., Ho L., Santa-Maria I., Diaz-Ruiz C., Wang J., Pasinetti G.M. Ultrastructural alterations of Alzheimer’s disease paired helical filaments by grape seed polyphenols. Neurobiology of Aging. 2012; 33(7): 1427-39

Wang J*., Santa-Maria I.*, Ksiezak-Reding H., Ho L., Pasinetti G.M. Grape Derived Polyphenols Attenuate Tau Neuropathology in a Mouse Model of Alzheimer's Disease. Journal of Alzheimer´s Disease. 2010; 22(2): 653-61. [*co-authors]

Santa-Maria I., Avila J., Rabano A. Differential gene expression analysis of human entorhinal cortex support a possible role of some extracellular matrix proteins in the onset of Alzheimer disease. Neuroscience Letters. 2010; 468 (3): 225-228.

Perez M*., Santa-Maria I.*, Gomez de Barreda E., Zhu X., Cuadros R., Roman Cabrero J., Sanchez-Madrid F., Dawson HN., Vitek MP., Perry G., Smith MA., Avila J. Tau, an inhibitor of deacetylase HDAC6 function. Journal of Neurochemistry. 2009; 109 (6): 1756-1766. [*co-authors]

Santa-Maria I., Santpere G., MacDonald M. J., Gomez de Barreda E., Felix Hernandez F., Moreno F. J., Ferrer I., Avila J. Coenzyme Q as an inducer in vivo of tau aggregation, tau filaments and Hirano bodies. Journal of Neuropathology and Experimental Neurology. 2008; 67 (5): 428-434.

Mondragón-Rodríguez S., Basurto-Islas G., Santa-Maria I., Mena R., Binder L. I., Avila J., Smith M. A., Perry G., García-Sierra F. Cleavage and Conformational Changes of Tau Protein Follow Phosphorylation During Alzheimer´s Disease. International Journal of Experimental Pathology. 2008; 89 (2): 81-90

Santa-Maria I., Hernandez F., Del Rio J., Moreno F.J., Avila J. Tramiprosate, a drug of potential interest for the treatment of Alzheimer's disease, promotes an abnormal aggregation of tau. Molecular Neurodegeneration. 2007; 2 (1): 17.

Santa-Maria I., Perez M., Hernandez F., Munoz V., Moreno F.J., Avila J. In vitro tau fibrillization: mapping protein regions. Biochimica et Biophysica Acta. 2006; 1762 (7): 683-692.

Santa-Maria I., Smith M.A., Perry G., Hernandez F., Avila J., Moreno F.J. Effect of quinones on microtubule polymerization: a link between oxidative stress and cytoskeletal alterations in Alzheimer's disease. Biochimica et Biophysica Acta. 2005; 1740 (3): 472-80.

Mendieta J., Fuertes M.A., Kunjishapatham R., Santa-Maria I., Moreno F.J., Alonso C., Gago F., Munoz V., Avila J., Hernandez F. Phosphorylation modulates the alpha-helical structure and polymerization of a peptide from the third tau microtubule-binding repeat. Biochimica et Biophysica Acta. 2005; 1721 (1-3): 16-26.

Santa-Maria I., Hernandez F., Martin C.P., Avila J., Moreno F.J. Quinones facilitate the self-assembly of the phosphorylated tubulin binding region of tau into fibrillar polymers. Biochemistry. 2004; 43 (10): 2888-97.

Current Projects

Our research has shown a specific microRNA, miR-219, is downregulated in AD. Using mammalian cell cultures and a novel transgenic Drosophila model, we have also found that miR-219 directly binds to the tau mRNA 3' untranslated region (UTR) and silences its expression at the post-transcriptional level. Moreover, in transgenic Drosophila flies we observed that miR-219 reduced tau toxicity, suggesting that miR-219 is part of a vital regulatory mechanism that prevents the deposition of tau. Furthermore, our bioinformatics analysis indicates miR-219 is also targeting Tau tubulin kinase 1 (TTBK1), Calcium/calmodulin-dependent protein kinase II (CaMKII), AMP-activated protein kinase (AMPK), and Glycogen synthase kinase 3 beta (GSK3β), which are all kinases implicated in the generation of abnormal hyperphosphorylated tau. We continue exploring the role of microRNAs in tau pathogenesis using Drosophila melanogaster (fruit fly) as an animal model. This work aims to characterize microRNA regulation of the expression of tau and the candidate kinases and to demonstrate that microRNAs modulate tau neurotoxicity using various CRISPR-edited and other transgenic flies we have developed. On the other hand, we are actively investigating the role microRNAs play in tau proteostasis regulation in mammalian cellular systems, in neuronal cell lines and neuronal primary cultures. In addition, we are currently investigating post-transcriptional molecular mechanisms that regulate tau expression and phosphorylation of tau in mice. We aim to determine the extent to which 3'UTR-microRNA interactions influence tau toxicity in a transgenic mouse model of AD-related tauopathy.

Honors and Awards

2008 - Spanish Royal Doctors Academy award
2009 - Neurological Diseases Research Centre Foundation and Queen Sofia Foundation’s Alzheimer’s Disease award
2012 - American Health Assistance Foundation Alzheimerʼs Disease Award
2013 - BrightFocus Foundation Alzheimerʼs Disease Award
2014 - Pilot Grant Award 
for Research on Alzheimer’s disease, aging, and related disorders
2015 - Alzheimer's Association New Investigator Research Grant
Committees , Council, and Professional Society Memberships

The New York Academy of Science
Society for Neuroscience

Tau, microRNAs, post-transcriptional regulation, Alzheimer’s disease, Tauopathies, neurodegeneration

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