Lysosomal Storage Disease Factors: the Work of Elizabeth F. Neufeld
Year: 2007
Type: article
Abstract: The Hurler Corrective Factor. Purification and Some Properties (Barton, R. W., and Neufeld, E. F. (1971) J. Biol. Chem. 246, 7773–7779) The Sanfilippo A Corrective Factor. Purification and Mode of Action (Kresse, H., and Neufeld, E. F. (1972) J. Biol. Chem. 247, 2164–2170) The Hunter Corrective Factor. Purification and Preliminary Characterization (Cantz, M., Chrambach, A., Bach, G., and Neufeld, E. F. (1972) J. Biol. Chem. 247, 5456–5462) Elizabeth Fondal Neufeld was born in 1928 in Paris, France. Her parents were Russian refugees who had settled in France after the Russian revolution. However, the impending occupation of France by the Germans forced the Fondal family to move to New York in 1940. Consequently, Neufeld attended Queens College in New York, where she received her B.S. in 1948. She then worked briefly as a research assistant to Elizabeth Russell at the Jackson Memorial Laboratory in Bar Harbor, Maine, before enrolling in graduate school at the University of Rochester. Due to personal reasons Neufeld moved to Maryland in 1951, where she served as a research assistant to Nathan Kaplan and Sidney Colowick at the McCollum-Pratt Institute at Johns Hopkins University. Colowick's research on NADH was the subject of a previous Journal of Biological Chemistry (JBC) Classic (1Pullman M.E. San Pietro A. Colowick S.P. JBC Classics. 1954; 206 (http://www.jbc.org/cgi/content/full/280/39/e36): 129-141Abstract Full Text PDF PubMed Google Scholar), and Kaplan will be featured in an upcoming JBC Classic. In 1952, Neufeld enrolled in graduate school again, this time at the University of California, Berkeley, where she studied with JBC Classic author William Zev Hassid (2Babad H. Hassid W.Z. JBC Classics. 1964; 241 (http://www.jbc.org/cgi/content/full/280/34/e31): 946-948Google Scholar). She received a Ph.D. in 1956 for her work on nucleotides and complex carbohydrates. Neufeld then did several years of postdoctoral research at Berkeley, first working with Dan Mazia on non-protein sulfhydryl compounds in mitosis and then returning to Hassid's laboratory to pursue research on substituted sugars, polysaccharides, and glycoproteins. In 1963, Neufeld moved to the National Institutes of Health (NIH), where she became a research biochemist at the National Institute of Arthritis, Metabolism, and Digestive Diseases. It was during her time at the NIH that Neufeld began her research on mucopolysaccharidoses (MPS) disorders, a group of lysosomal storage diseases in which mucopolysaccharides cannot be stored or metabolized properly. Hurler syndrome and Hunter syndrome are two MPS disorders in which partially degraded dermatan sulfate and heparan sulfate accumulate in lysosomes. Affected individuals usually die from the diseases by age 15. It was accepted dogma in the early 1960s that mucopolysaccharides accumulate in these diseases because of aberrant regulation of their synthesis resulting in overproduction. At the NIH, Neufeld began to study mucopolysaccharide turnover in cultured fibroblasts from people with Hurler or Hunter syndrome by incorporating radioactive sulfate into newly synthesized mucopolysaccharides and studying their degradation with chase experiments. She showed that the defects in Hurler and Hunter syndromes were due to decreased degradation of the mucopolysaccharides and their resulting accumulation in lysosomes rather than an overproduction of the sugars (3Fratantoni J.C. Hall C.W. Neufeld E.F. The defect in Hurler's and Hunter's syndromes: faulty degradation of mucopolysaccharide. Proc. Natl. Acad. Sci. U. S. A. 1968; 60: 699-706Crossref PubMed Scopus (233) Google Scholar). Subsequently, Neufeld found that Hurler syndrome could be corrected by a macromolecular factor derived from fibroblasts or urine from donors who did not have Hurler syndrome. Her purification and characterization of this factor is discussed in the first JBC Classic reprinted here. The factor was purified 1000-fold from normal human urine. From her experiments, Neufeld surmised that the Hurler factor accelerates degradation of stored sulfated mucopolysaccharides. When an assay became available for α-l-iduronidase in 1972, Neufeld was able to show that the corrective factor for Hurler syndrome was, in fact, α-l-iduronidase and that this syndrome, as well as the Scheie syndrome, was due to a deficiency of that enzyme (4Bach G. Friedman R. Weissmann B. Neufeld E.F. The defect in the Hurler and Scheie syndromes: deficiency of α-l-iduronidase. Proc. Natl. Acad. Sci. U. S. A. 1972; 69: 2048-2051Crossref PubMed Scopus (170) Google Scholar). As reported in the second JBC Classic, Neufeld found a similar factor for Sanfilippo syndrome, a lysosomal storage disease marked by impaired degradation of heparan sulfate. The life span of children with this disorder does not usually extend beyond late teens to early twenties. Sanfilippo patients fall into four subgroups, designated A through D, deficient in one of four factors. Neufeld purified the Sanfilippo A corrective factor 850-fold from normal human urine. She found that incubation of stored mucopolysaccharide with the purified factor resulted in release of inorganic sulfate, suggesting that the Sanfilippo A factor was a heparan sulfate sulfatase. This proved to be correct. In the final JBC Classic, Neufeld returned to her research on Hunter syndrome and presented the purification of the Hunter corrective factor from normal human urine. She found that the factor accelerates the degradation of labeled dermatan sulfate as well as exogenously added proteodermatan [35S]sulfate. Neufeld eventually determined that the Hunter corrective factor was iduronate sulfatase (5Bach G. Eisenberg F. Cantz M. Neufeld E.F. The defect in the Hunter syndrome: deficiency of sulfoiduronate sulfatase. Proc. Natl. Acad. Sci. U. S. A. 1973; 70: 2134-2138Crossref PubMed Scopus (166) Google Scholar). In 1973 Neufeld was named chief of the NIH Section of Human Biochemical Genetics, and in 1979 she was named chief of the Genetics and Biochemistry Branch of the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases (NIADDK). She served as deputy director of NIADDK's Division of Intramural Research from 1981 to 1983. In 1984 Neufeld returned to the University of California, this time the Los Angeles campus, as chair of the Biological Chemistry Department. She continues to do research at UCLA today. Neufeld has chaired the Scientific Advisory Board of the National MPS Society since 1988 and was president of the American Society for Biochemistry and Molecular Biology in 1992. She was elected to both the National Academy of Sciences and the American Academy of Arts and Sciences in 1977 and was named a fellow of the American Association for Advancement in Science in 1988. In recognition of her scientific achievements she was awarded the Hildebrand Award in 1975, the Gairdner Foundation Award in 1981, the Lasker Award in 1982, the International Society for Clinical Enzymology J. Henry Wilkinson Memorial Award in 1983, the Franklin Institute's Elliot Cresson Medal in 1984, the Wolf Prize in Medicine in 1988, the National Medal of Science in 1994, and the Christopher Columbus Discovery Award for Biomedical Research in 1992. She was named California Scientist of the Year in 1990. 1Biographical information on Elizabeth F. Neufeld was taken from Ref. 6Hirschhorn K. The William Allan Memorial Award. Am. J. Hum. Genet. 1983; 35: 1077-1080Google Scholar. 1Biographical information on Elizabeth F. Neufeld was taken from Ref. 6Hirschhorn K. The William Allan Memorial Award. Am. J. Hum. Genet. 1983; 35: 1077-1080Google Scholar.
Source: Journal of Biological Chemistry
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1567859361