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Neuroscience Graduate Program at UCSF
Human Genetics in Neurodegenerative Disease
We are interested in understanding the mechanisms of various diseases involving the nervous system. In particular, there are two classes of neurodegenerative diseases that we are focusing on: polyglutamine diseases and demyelinating degenerative diseases. In addition, we are also interested in the Human circadian rhythmicity. Our group has been using human genetic tools to identify genes involved in these disorders. Studying the disease mechanisms following the discovery of the genes will lead to unraveling of the pathogenesis of these disorders.
Polyglutamine diseases: Over the past decade, expanded TNR sequences have been recognized as a significant source of mutation in the human genome. More than a dozen neurodegenerative diseases are known to contain repeat expansions within their associated genes. One class of mutation, the expansion of a CAG repeat encoding a polyglutamine (polyQ) tract, has been associated with at least eight different neurodegenerative disorders. Spinocerebellar ataxia (SCA) is a heterogeneous group of diseases that fall into this category. The repeat tracts within these genes display common size ranges for both normal as well as mutant alleles. This has led to the hypothesis that expanded polyQ tracts may be toxic to cells in the CNS. Like other TNR expansion diseases, anticipation is present in the SCAs and intranuclear inclusions (INIs) are seen in affected cells from SCA patients. There are two forms of SCAs that we are working on: 1) Spinocerebellar Ataxia 7, 2) Spinocerebellar Ataxia 4.
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. My long-term goal is to understand molecular mechanism of dysmyelination in these diseases (and of myelin synthesis, degeneration, and regeneration in general).
Human Circadian Rhythm Genetics: Another area of my research interest is in the study of circadian rhythm. 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. 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. Various agents including caffeine and alcohol also confound one's ability to understand the inherent rhythms dictating humans' activities. We are in the process of identifying mutations that are involved in regulation of human rhythmicity. 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.Cloning of SCA4 gene
Cloning of ADLD gene
Identifying the chromosome breakpoint associated with Multiple Sclerosis
Study disease mechanism of SCA7
Study human circadian rhythm -Identify mutations as well as study the circadian rhythm mechanismYiguo Shen
Post Doctoral Researcher
Ph.D.
Jimmy Holder
Post Doctoral Researcher
M.D., Ph.D.
Sang-Soep Nahm
Post Doctoral Researcher
DVM., Ph.D.
Ying Xu
Post Doctoral Researcher
M.D., Ph.D.
Archana Shenoy
Graduate Student
B.S.
Sonja Hombach
Post Doctoral Researcher
Ph.D.
Ying Tong
Post Doctoral Researcher
Ph.D.
Joel Rawson
Post Doctoral Researcher
Ph.D.
Devon Ryan
Graduate Student
B.S.
Daesung Shin
Post Doctoral Researcher
Ph.D.
Shu-Ting Lin
Post Doctoral Researcher
M.D., Ph.D.
Eva LaDow
Graduate Student
B.A.
Krista Kaasik
Post Doctoral Researcher
Ph.D.
Lifang Mao
Post Doctoral Researcher
M.D., Ph.D.
Kevin Magruder
Clinical Coordinator
B.A.
Joan Carroll
Clinical Coordinator
B.S.
Liqun Qiu
Research Associate
B.S.
Jeff Cheung
Research Associate
Ying Zhang
Lab Assistant
Quasar Padiath
Post Doctoral Researcher
M.B.B.S., Ph.D.
Jan Freudenberg
Post Doctoral Researcher
M.D.
Hsien-Yang Lee
Post Doctoral Researcher
Ph.D.
Junko Nakayama
Post Doctoral Researcher
M.D., Ph.D.
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.
Phone
415-502-2948
Physical Address
UCSF-Neurology
Fu and Ptacek Laboratories
Rock Hall
1550 4th Street
Room 548F
San Francisco, CA 94158
Mailing Address
UCSF-Neurology
Fu and Ptacek Laboratories
Rock Hall
1550 4th Street
Box 2922
San Francisco, CA 94143
For Internal Campus Mail
Box 2922
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