Neuroscience Graduate Program

Neuroscience Graduate Program at UCSF

Faculty - Ying-Hui Fu, Ph.D.

Human Genetics in Neurodegenerative Disease

Research Description

We are interested in understanding the mechanisms of various conditions involving the nervous system. In particular, we are focusing on demyelinating degenerative diseases. In addition, we are also interested in the Human circadian rhythmicity and sleep behavior. Our group has been using human genetic tools to identify genes involved in these phenotypes. Studying the molecular mechanisms following the discovery of the genes will lead to unraveling of the pathogenesis of these and their related conditions.

Multiple Sclerosis: Multiple sclerosis is a common, often severe neurologic disorder for which the cause, cure and prevention are unknown and for which no specific diagnostic test exists. We are currently working on two projects that relate to demyelinating degenerative diseases of the nervous system. 1) Autosomal dominant leukodystrophy (ADLD) is clinically similar to the chronic progressive form of MS. Misdiagnosis of ADLD patients as having MS is common although ADLD and MS are readily distinguishable at autopsy. 2) Multiple Sclerosis Associated with a Chromosomal Translocation This phenotype is co-segregating with a balanced chromosome translocation. We are also interested in identifying and characterizing miRNAs that are important for healthy myelin. My long-term goal is to understand molecular mechanisms of maintaining and regenerating healthy myelin.

Human Circadian Rhythm and Sleep Genetics: Another area of my research interest is in the study of circadian rhythm and Sleep. Circadian rhythm is one of the best models for studying human behavior. When we say "Geneitcs is everything", it may not be so far-fetched in truth if we come to recognize how much our behaviors are impacted by our genetic composition. Many of our physiological processes including heart beat, blood pressure, body temperature, and endocrine functions are subject to circadian regulation. However, the regulation of the overall behavior of an organism is the most overt and intriguing manifestation of circadian rhythmicity. Considering we spend one third of our lives in the state of sleep, our understanding of sleep regulation is very limited. The pursuit of the genetic and molecular basis of behavior is extremely complex because of the wide variation in "normal" individuals. Furthermore, behaviors such as sleep are confounded by social and familio-cultural influences that frequently lead us to override our biological clock and stay up later or to wake up earlier than we otherwise would or shorten sleep duration. Various agents including caffeine and alcohol also confound one's ability to understand the inherent rhythms and sleep homeostasis dictating humans' activities. We have identified many and are still in the process of identifying more mutations that are involved in regulation of human rhythmicity and sleep. My long-term goal for this particular project is that as we find more mutations that are affecting human sleep pattern, we will characterizing these mutations to assist us understand human circadian clock and sleep regulation.

Current Projects

Identify human sleep genes

Molecular studies of human sleep regulation

Molecular studies of human circadian rhythm regulatory mechanism

Characterize mouse models of de/dys-myelinating disease

Characterize miRNAs that are important for healthy myelin

Lab Members

William Hallows, Postdoctoral Fellow
Mary Heng, Postdoctoral Fellow
Shen-Yi Bruce Howng, Postdoctoral Fellow
Angela Huang, Postdoctoral Fellow
Yong Huang, Postdoctoral Fellow
Krista Kaasik, Postdoctoral Fellow
Christine Cheung, Postdoctoral Fellow
Mary Lange, Administrative Personnel
Hsien-Yang Lee, Postdoctoral Fellow
Shu-Ting Ling, Postdoctoral Fellow
Emily Quinn, Clinical Coordinator
Jonathan Russell, Graduate Student
Sami Gritli, Postdoctoral Fellow
Jenise Wong, Clinical Fellow
Linda Zhang, Laboratory Assistant
Luoying Zhang, Postdoctoral Fellow
Jeff Cheung, Laboratory Assistant
Ying Zhang, Laboratory Assistant

Selected Publications

Link to Publications via PubMed

Fu Y-H, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG Jr, Warren ST, Oostra BA, Nelson DL, Caskey CT. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 1991 Dec 20, 67 (6):1047-1056.

Fu Y-H, Pizzuti A, Fenwick,Jr., RG, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, DeJong P, Wieringa B, Korneluk R, Perryman BM, Epstein HF, Caskey CT. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 1992, 255:1256-1258.

Caskey CT, Pizzuti A, Fu Y-H, Fenwick RG Jr, Nelson DL. Triplet repeat mutations in human disease. Science 1992 May 8, 256 (5058):784-789.

Fu Y-H, Friedman DL, Richards S, Pearlman JA, Gibbs RA, Pizzuti A, Ashizawa T, Perryman MB, Fenwick RG Jr, Caskey CT. Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science 1993 Apr 9, 260 (5105):235-238.

Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wejsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995, 269:973-977.

Fu Y-H, Yu CE, Oshima J, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD (The first three authors contributed equally). Positional cloning of the Werner’s syndrome gene. Science 1996 Apr 12, 272 (5259):258-261.

Coffeen CM, McKenna CE, Koeppen AH, Plaster NM, Maragakis N, Mihalopoulos J, Schwankhaus JD, Flanigan KM, Gregg RG, Ptáček LJ, Fu Y-H. Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31. Hum Mol Genet. 2000 Mar 22, 9(5):787-793.

Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptáček LJ, Fu Y-H. An hPer2 phosphorylation site mutation in familial advanced sleep-phase syndrome. Science 2001 Feb 9, 291 (5506):1040-1043.

Einum DD, Townsend JJ, Ptáček LJ, Fu, Y-H. Ataxin-7 expression analysis in controls and spinocerebellar ataxia type 7 patients. Neurogenetics 2001 Mar, 3(2):83-90.

Plaster NM, Tawil R, Tristani-Firouze M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr., Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu Y-H, Ptáček LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 2001, 105:511-519.

Matilla A, Gorbea C, Einum DD, Townsend J, Michalik A, van Broeckhoven C, Jensen CC, Murphy KJ, Ptáček LJ, Fu Y-H. Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex. Hum Mol Genet. 2001 Nov 15, 10(24):2821-2831.

Einum D, Clark AM, Townsend JJ, Ptáček LJ, Fu Y-H. A novel central nervous system-enriched spinocerebellar ataxia type 7 gene product. Arch Neurol. 2003, 60:97-103.

Ptáček LJ, Fu YH. Channels and Disease: Past, Present, and Future. Arch Neurol. 2004 Nov; 61(11):1665-8.

Lee HY, Xu Y, Huang Y, Ahn AH, Auburger GW, Pandolfo M, Kwieciński H, Grimes DA, Lang AE, Nielsen JE, Averyanov Y, Servidei S, Friedman A, Bogaert PV, Abramowicz MJ, Bruno MK, Sorensen BF, Tang L, Fu YH, Ptáček LJ. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet. 2004 Dec 15;13(24):3161-70. Epub 2004 Oct 20.

Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptáček LJ, Fu YH. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature. 2005 Mar 31;434(7033):640-4.

Ying-Hui Fu, Ph.D.