Assistant Professor, The Saul R. Korey Department of Neurology
Dr. Aldrin Molero M.D., Ph. D., received his medical degree at the University of Zuila in Venezuela and completed his Ph.D at Albert Einstein College of Medicine. He continues to teach and research with a goal to define the normal roles of Huntingtin in neural stem cell-mediated striatal neurogenesis and the effects of mutant Huntingtin in brain development and Huntington’s disease pathogenesis.
Our limited knowledge of the normal roles of Huntingtin (Htt) in neural structures affected in the disease has contributed to the slow rate of progress in defining Huntington's disease pathogenesis. Several lines of evidence suggest that Htt has important roles in developmental striatal neurogenesis. The purpose of my studies is to define the normal roles of Htt in striatal development. My central hypothesis is that Htt plays pivotal roles in Neural Stem Cell (NSC)-mediated striatal neurogenesis and the functional compartmentalization of the striatum. Furthermore, I postulate that disruption of these Htt-associated neural functions leads to the elaboration of developmentally deregulated medium-size spiny neurons (MSNs) with an enhanced susceptibility to stressors, thus contributing to HD-associated profiles of cellular vulnerability. That is, the abnormal neural development associated to the loss of Huntingtin function, lead to cells that are more susceptible to stress, and thus, to death, thus explaining the regional profiles of neuronal vulnerability displayed by Huntington’s disease. To substantiate this hypothesis, I am performing conditional ablation studies of Htt (employing a floxed Wt-Htt mouse) in selective neural developmental species during embryogenesis and defining the developmental and late-life consequences of these genetic manipulations.
These studies will define the stage-specific developmental roles of Htt in the program of NSC-mediated striatal MSN neurogenesis. Moreover, these studies will provide important perspectives into the mechanisms mediating the differential profiles of neuronal vulnerability in HD, especially with regard to the role of the loss-of-developmental function mechanism in HD pathogenesis. Further, these studies have the potential to shift the focus of current research by identifying a novel window for the study of HD pathogenesis and for the further development of restorative interventions at a time when irrevocable neurodegenerative changes have not yet occurred. From a broader perspective, the insights obtained from these studies may also have important implications for our understanding of other neurodegenerative diseases, particularly those associated with abnormal repeat expansions.
Molero AE., Gokhan S., Gonzalez S., Feig JL., Alexandre L., Mehler MF. Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington’s disease. (2009): Proceedings of the National Academy of Sciences USA. 2009; Proc Natl Acad Sci U S A. 106(51): 21900-21905.
Abrajano JJ, Qureshi IA, Gokhan S, Molero AE, Zheng D, Bergman A, Mehler MF. Corepressor for element-1-silencing transcription factor preferentially mediates gene networks underlying neural stem cell fate decisions. Proc Natl Acad Sci U S A. 2010; 107(38): 16685-90
Yung SY, Gokhan S, Jurcsak J, Molero AE, Abrajano JJ, Mehler MF. Differential modulation of BMP signaling promotes the elaboration of cerebral cortical GABAergic neurons or oligodendrocytes from a common sonic hedgehog-responsive ventral forebrain progenitor species. Proc Natl Acad Sci U S A. 2002; 99 (25):16273-8.
Molero AE, Pino-Ramírez G, Maestre GE. Modulation by age and gender of risk for Alzheimer's disease and vascular dementia associated with the apolipoprotein E-epsilon4 allele in Latin Americans: findings from the Maracaibo Aging Study. Neurosci Lett. 2001; 307 (1):5-8.
Molero AE, Pino-Ramirez G, Maestre GE. High Rates of dementia in a Caribbean population. Neuroepidemiology. 2007; 29(1-2):107-12.
Chacon IJ., Molero AE., Pino-Ramirez G., Luchsinger JA., Lee JH., Maestre GE. Risk of Dementia Associated with Elevated Plasma Homocysteine in a Latin American Population. International Journal of Alzheimer’s Disease. Volume 2009 (2009), Article ID 632489 (Open Access Journal: http://www.sage-hindawi.com/journals/ijad/2009/632489.html).
Molero AE, Altimari CC, Duran DA, Garcia E, Pino-Ramirez G, Maestre GE. Total plasma homocysteine values among elderly subjects: findings from the Maracaibo Aging Study. Clin Biochem. 2006; 39 (10):1007-15.
Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.
Albert Einstein College of Medicine
Rose F. Kennedy Center
1410 Pelham Parkway South , Room 401
Bronx, NY 10461