Sheng Zhang, Ph.D.
Assistant Professor, Center for Metabolic and Degenerative DiseasesSheng.Zhang@uth.tmc.edu
With a rapidly growing aging population, society is facing a mounting challenge from aging-related neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Our laboratory is interested in two questions that are important for these brain disorders: (1) what is the normal function of disease-causative genes?; (2) what regulates the formation of aggregates? We are using Drosophila, commonly known as the fruit fly and one of the best-studied genetic organisms, as a model system to address these questions. Currently our study focuses on Huntington’s (HD) and Parkinson’s diseases.
B.S. Beijing University, Beijing, China
M.S. Shanghai Institute of Biochemistry, Chinese Academy of Sciences, Shanghai, China
Ph.D. Yale University School of Medicine, New Haven, CT
Postdoc Harvard Medicine School, Boston, MA
I. Functional Dissection of Huntingtin Protein
Huntington's disease (HD) is caused by an abnormal expansion of a polyglutamine tract in the Huntingtin (Htt) protein. Recent studies suggest that dysfunction of normal Huntingtin contributes to disease pathogenesis; however, the endogenous function of Huntingtin is still largely unknown. To address this question, we have deleted the Huntingtin homolog in Drosophila (dhtt), and found that its normal function is essential for maintaining the mobility and long-term survival of adult animals. Further, removal of endogenous dhtt can significantly accelerate the neurodegenerative phenotype associated with a Drosophila model of HD. We are currently taking advantage of the abundant experimental tools available in Drosophila to dissect the endogenous function of this enigmatic protein.
II. Understanding the Regulation of Aggregates Formation
Neurodegenerative diseases are characterized by the presence of protein aggregates in the brain. Formation of aggregates is believed to be a dynamic process involving multiple intermediate species of different sizes and conformations (e.g., oligomers, prefibrils, fibrils), and their effects on neurodegeneration may vary from toxic to protective. Understanding the regulation of aggregates formation will be important in finding effective treatments for these diseases. We have established a cell-based quantitative assay that allows automated measurement of aggregates within Drosophila cells. Using this assay, we have carried out a genome-wide RNA interference (RNAi) screen and identified a group of genes that can modulate aggregation of mutant Huntingtin protein. These genes are involved in diverse cellular processes such as protein folding, trafficking and signaling. We are using these isolated aggregation modulators as entry points to systematically study the molecular network regulating both aggregates formation and neurotoxicity.
Through these studies, we aim to establish a research platform that combines multi-disciplinary approaches to understand the pathogenesis of these diseases and to identify therapeutic targets for the prevention and cure of these devastating brain disorders.
1. Xu T, Wang W, Zhang S, Stewart RA, Yu W. (1995). Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development. 121(4):1053-63.
2. Hu G, Zhang S, Vidal M, Baer JL, Xu T, Fearon ER. (1997). Mammalian homologs of seven in absentia (sina) regulate DCC via the ubiquitin-proteasome pathway. Genes & Development. 11(20):2701-14.
3. Theodosiou NA, Zhang S, Wang WY, Xu T. (1998). slimb coordinates wg and dpp expression in the dorsal-ventral and anterior-posterior axes during limb development. Development 125(17):3411-3416.
4. Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, Xu T. (1999). Human homologue of the Drosophila melanogaster lats tumor suppressor modulates CDC2 activity. Nature Genetics, 21(2):177-81.
5. Zhang S, Xu L, Lee J, Xu T. (2002). Drosophila Atrophin homolog functions as a transcriptional co-repressor in multiple developmental processes. Cell, 108 (1): 45-56.
6. Zhang, S., Feany, M. B., Saraswati, S., Littleton, J. T., Perrimon, N. (2009). Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington's disease model. Disease Models & Mechanisms 2 : 247-266.