Research Investigator Profile
Antonio Valencia, PhD
- Instructor in Neurology,
Harvard Medical School
- Assistant in Neuroscience,
Massachusetts General Hospital
- Co-Director, of Mouse Behavior Core
My research focuses on the molecular mechanisms of neurodegeneration in Huntington’s disease (HD), including oxidative stress, signaling pathways, cellular membranes, and cell death. The main model for my studies is a homozygous HD mouse model expressing mutant huntingtin (140-Q repeats), which causes HD. I have demonstrated that primary HD neurons die more rapidly than control neurons, which is prevented by blocking the early increase of reactive oxygen species (ROS). I identified the source of ROS in HD, the NADPH oxidase or NOX2, which generates superoxide inducing an elevation of ROS. NOX activity is higher in HD neurons and brain tissue than controls, however the mechanism of activation is unknown and still under investigation. Interestingly, pre-symptomatic HD human brains have higher levels of NOX activity than advanced HD brains. Furthermore, oxidation of synaptic proteins occurs in HD mouse brains. Currently, I am studying a crossbreed mouse model HD/NOX- (Q140 HD with a NOX2 knockout). Using HD/NOX2- mice shows that NOX2 activation induces ROS increase and neurodegeneration in HD. NOX2 activation occurs in lipid rafts, therefore my interest on studying these micro-domains in HD. There are deficits in lipid rafts components in HD, including neurons, mouse and human brain. Now, I am designing experiments directed to treat HD mice with small molecules and follow up using behavior tests and biochemical markers. My goal is to find potential targets that can be helpful to find a therapy for HD.
View poster: Early Increase in the NADPH-Oxidase (NOX2) Activity Contributes to Oxidative Stress and Neurodegeneration in Huntington's Disease - PDF
Learn more about the Laboratory of Cellular Neurobiology.
|Research interests||Neurodegenerative diseases. Oxidative stress. Lipid rafts and lipid biology. Synaptic function. Cell death. Apoptosis. Neurons. Neurodegeneration. Genetically modified mice models. Animal behavior.|
|Research techniques||Culture of primary neurons, cell lines and stem cells (neuro progenitor stem cells). Confocal microscopy. Enzymatic assays. Cellular fractionation (synaptosomes, endosomes, lipid rafts, mitochondria). Enzymatic activity. Animal models (transgenic and knock-in). Live cell imaging. Determination of oxidative stress and oxidation damage. Glutamate release. Apoptotic markers. Cell signaling. Dissection and collection of brain tissue. Breeding and housing transgenic and knock-in mice. Animal behavior. Therapeutic experiments in vivo (animal trials).|
|Diseases studied||Huntington's disease|
|Selected publications||1. Valencia A, Sapp E, Kimm JS, McClory H, Reeves PB, Alexander J, Ansong KA, Masso N, Frosch MP, Kegel KB, Li X and DiFiglia M. Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington’s disease. Human Molecular Genetics. 2012. Accepted, in press. doi: 10.1093/hmg/dds516.
2. Ritch JJ, Valencia A, Alexander J, Sapp E, Gatune L, Sangrey GR, Sinha S, Scherber CM, Zeitlin S, Sadri-Vakili G, Irimia D, Difiglia M, Kegel KB. Multiple phenotypes in Huntington’s disease mouse neuronal stem cells. Molecular and Cellular Neuroscience. 2012. May 50(1): 7081.
3. Sapp E., Valencia A., Li X., Aronin N., Kegel K.B., VOnsattel JP. Young A.B., Wexler N. and DiFiglia M. Native mutant huntingtin human brain: evidence for prevalence of full length monomer. Journal of Biological Chemistry. 2012. 287(16):13487-99.
4. Valencia A., Reeves P.B., Sapp E., Li X., Alexander J., Masso N., Li X., Kegel and DiFiglia M. Reagents that curb neuronal death from Huntington’s disease also curb oxidative stress. Neuroreport. (2012). Jan;4,23(1):10-15.
5. Li X.*, Valencia A.*, Sapp E., Masso N., Alexander J., Reeves P., Kegel K.B., Aronin N., and DiFiglia M. Aberrant Rab11-dependent Trafficking of the Neuronal Glutamate Transporter EAAC1 Causes Oxidative Stress and Cell Death in Huntington's Disease. Journal of Neuroscience. (2010). March 31, 2010, 30(13):4552-4561. *Equal contribution.
6. Valencia A., Reeves P.B., Sapp E., Li X., Alexander J., Kegel K.B., Chase K., Aronin N. and DiFiglia M. Mutant huntingtin accumulates in neuronal lipid rafts in of a pre-symptomatic mouse model of Huntington’s disease. Journal of Neuroscience Research. (2010). Jan;88(1):179-90.
|NCBI PubMed link||NCBI PubMed publications|
|E-mail address||Avalencia1@partners.org email@example.com|
|Lab mailing address||
MassGeneral Institute for Neurodegenerative Disease (MIND)