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Robert Nussbaum, MD
Human Genetic Analysis of Parkinson's disease and other disorders
Selected Publications | Complete Publications

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Dr. Nussbaum’s laboratory studies genetic contributions developmental and neurodegenerative disorders. His two major areas of concentration are Lowe syndrome and Parkinson disease. Lowe syndrome, formally known as Lowe oculocerebrorenal syndrome (OCRL), is a rare X-chromosome-linked disorder that can cause mental retardation, seizures, cataracts, and kidney disease in young children. Most Lowe syndrome patients die in their teens or twenties. Parkinson disease is a slowly progressive disease of the nervous system, which strikes an estimated 50,000 mostly older Americans each year. It is second only to Alzheimer’s disease among the most common neurodegenerative diseases in the developed world.

In 1992, Dr. Nussbaum identified a defective gene that causes Lowe syndrome. The gene, OCRL1, codes for phosphatidylinositol-4, 5-bisphosphate 5-phosphatase-an enzyme that acts primarily in the Golgi apparatus of the cell and may be involved in protein processing and transport. Dr. Nussbaum’s lab developed a clinically useful enzyme test for Lowe Syndrome, carried out the first prenatal diagnosis of the condition by enzyme assay, and pioneered the delivery of genetic services and counseling, including carrier testing, to families of Lowe syndrome patients. Determining the enzyme’s normal function and why disabling it affects so many apparently unrelated organ systems could point to possible treatments. Interestingly, OCRL1 knockout mice do not develop Lowe syndrome symptoms. Dr. Nussbaum is investigating the role of an autosomal paralog for OCRL1, INPP5B, as a possible compensating gene and gene product in mice.

In his Parkinson disease work, Dr. Nussbaum’s laboratory seeks to understand the range of genes that can contribute to this disorder. Scientists long believed that Parkinson was not an inheritable disease. In 1997, Dr. Nussbaum and collaborators within and outside NHGRI identified a missense mutation in the alpha-synuclein gene (SNCA) as the cause of hereditary, early onset Parkinson disease in an Italian-American family. In 2003, collaborating with researchers John Hardy and Andy Singleton at the National Institute on Aging, Dr. Nussbaum and his colleague Dr. Amalia Dutra helped the NIA researchers identify a triplication of the SNCA in one large family affected by early-onset Parkinson disease. When Lewy bodies- protein aggregates that are a defining characteristic of Parkinson disease- were found to be composed primarily of alpha-synuclein, the link between mutations in SNCA and Parkinson disease was clearly established and provide strong evidence that mutations that change alpha-synuclein’s properties or cause it to be overexpressed may be involved in Parkinson disease pathogenesis. Finally, Dr. Nussbaum’s laboratory has demonstrated a defect in phospholipid metabolism in mouse brains lacking alpha-synuclein. In particular, a deficiency of cardiolipin was seen, associated with a mild defect in mitochondrial electron transport chain function. The normal function of alpha-synuclein has been obscure and these results point to a definitive link between this protein and mitochondrial function, which has long been implicated in Parkinson disease.

Dr. Nussbaum’s group has engineered several transgenic mice that express mutant human alpha-synuclein. Interestingly, mice that express only mutant human alpha-synuclein develop severe, rapid neurological deterioration, particularly in the spinal cord; mice that express both the mouse and the human protein develop mild deterioration. The investigators still do not know why and how the mouse protein protects against neurodegeneration.

Selected Publications
Attree, OF, Olivos, IM, Okabe, I, Bailey, LC, Nelson DL, Lewis, RA, McInnes, RR, and Nussbaum, R.L. The Lowe Oculocerebrorenal syndrome gene encodes a novel protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 358:239-242,1992.

Olivos-Glander, I.M., Jänne, P.A., and Nussbaum, R.L. The oculocerebrorenal syndrome gene product is a 105 kd protein localized to the golgi complex, Amer J Hum Genet, 57:817-823, 1995.

Suchy, S.F., Olivos-Glander, I.M., and Nussbaum, R.L. Lowe’s Syndrome, a deficiency of a phosphatidylinositol 4,5 bisphosphate 5-phosphatase in the Golgi apparatus. Hum Molec Genet, 4:2245-2250, 1995.

Polymeropoulos, MH, Higgins, JJ, Golbe, LI, Johnson, WG, Ide, SE, DiIorio, G, Sanges, G, Stenroos, ES, Pho, LT, Schaffer, AA, Lazzarini, AM, Nussbaum, RL, and Duvoisin, RC Mapping of a Gene for Parkinson’s Disease to Chromosome 4q21-q23, Science, 274:1197-1199, 1996

Polymeropoulos, MH , Lavedan, C ,Leroy, E, Ide, SE,Dehejia, A, Dutra, A, Pike,B, Root, H,

Rubenstein, J, Boyer, R, Stenroos, ES, Chandrasekharappa, S, Athanassiadou, A, Papapetropoulos, T, Johnson, WG, Lazzarini, AM, Duvoisin, RC, Di Iorio, G, Golbe, LI, Nussbaum, R.L.. Mutation in the a -Synuclein Gene Identified in Families with Parkinson's Disease. Science 276:2045-2047, 1997.

Jänne, PA, Suchy, SF,Bernard, D, MacDonald, M, Crawley, J, Grinberg, A, Wynshaw-Boris, A, Westphal, H, and Nussbaum, R.L.. Functional overlap between murine Inpp5b and OcR.L.1 may explain why deficiency of the murine ortholog for OCR.L.1 does not cause Lowe syndrome in mice. J Clin Invest, 101:2042-2053, 1998.

Dressman, MA, Olivos-Glander, IM, Nussbaum, R.L., Suchy SF. OcR.L.1, a PtdIns(4,5)P 2 5-phosphatase is localized to the trans-golgi network of fibroblasts and epithelial cells. J Histochem Cytochem. 48:179-90, 2000.

Ellis CE, Schwartzberg PL, Grider TL, Fink DW and Nussbaum R.L.. Alpha-Synuclein is Phosphorylated by Members of the Src Family of Protein Tyrosine Kinases, J Biol Chem, 276:3879-3884, 2001.

Hellsten, E, Evans, JP, Bernard,DJ, Jänne PA, Nussbaum, R.L.. Disrupted sperm function and fertilin  processing in mice deficient in the inositol polyphosphate 5-phosphatase Inpp5b. Dev Biol, 240:641-653, 2001.

Chiba-Falek, O., Nussbaum, R.L. Effect of allelic variation at the NACP-Rep1 repeat upstream of the ( a -synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet, 10(26):3101-9, 2001.

Hellsten,E, Bernard, DJ, Owens,JW, Eckhaus, M, Suchy, SF, and Nussbaum, R.L. Perturbations in cell adhesion and endocytosis in mice deficient in the inositol polyphosphate 5-phosphatase (Inpp5b), Biol Of Reproduction 66:1522-30, 2002 .

Cole, N.B., Murphy, D.D., Grider, T., Rueter, S., Brasaemle, D. and Nussbaum, R.L. Lipid Droplet Binding and Oligomerization Properties of the Parkinson's Disease Protein Alpha-Synuclein, J Biol Chem, 277:6344-52, 2002.

Sotiriou,S, Gispert, S, Cheng, J, Wang, Y-H, Chen, A, Hoogstraten-Miller, S, Miller, GF, Levine, MA, Guttentag, SH and Nussbaum, R.L.. Ascorbic acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival, Nature Med, 8(5):514-7, 2002.

Cabin, DE, Shimazu, K, Murphy, DD, , Cole, NB, Gottschalk, W, McIlwain, KC, Orrison, BM, Chen, A, Ellis, CE, Paylor, R, Lu, B, and Nussbaum, R.L.. Synaptic vesicle depletion correlates with attenuated synaptic responses to low frequency stimulation in mice lacking ( a -synuclein, J. Neurosci 22(20):8797-807, 2002.

Suchy, S.F. and Nussbaum, R.L. The deficiency of the OCRL.1 PIP 2 5-phosphatase in Lowe syndrome affects actin polymerization, Am J Hum Genet, 71:1420-1427, 2002 .

Gispert, S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-clement J, Korf H-W, Deller T, Braak H, Auburger G, and Nussbaum, RL. Substantia nigra pathology and abnormal motor behavior in transgenic mice expressing mutant A53T human alpha-synuclein, Molec Cell Neurosci, 24:419-29, 2003 .

Chiba-Falek, O, Touchman, JM and Nussbaum, RL : Sequence variation at the NACP-Rep1 repeat upstream of the a -synuclein gene (SNCA) , Human Genetics 113(5):426-31,2003.

S ingleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R , Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K. Alpha-Synuclein locus triplication causes Parkinson's disease. Science 302:841, 2003.

Cabin DE, Gispert-Sanchez, S, Murphy D, Auburger, G, Myers R, Nussbaum RL Exacerbated synucleinopathy in mice expressing A53T SNCA on a Snca null background. Neurobiology of Aging, 26(1):25-35, 2005.

Hoopes RR, Shrompton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL and Scheinman SJ: Dent disease with mutation in OCRL1, Amer J Hum Genet 76:260-267, 2005 .

Cole NB, Murphy D, Leibowitz J, diNoto L, Levine RL and Nussbaum RL: Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofilaments and filaments, J Biol Chem 280(10):9678-90, 2005

Chiba-Falek , O, Kowalak, JA, Smulson, ME, and Nussbaum, RL. Regulation of a -synuclein expression by Poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene, Amer J Hum Genet 76(3):478-92, 2005.

Ellis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, Barcelo-Coblijn GC and Nussbaum RL. Mitochondrial Lipid Abnormality and Electron Transport Chain Impairment in Mice Lacking a-synuclein. Mol. Cell. Biol, 25:10190-10201, 2005.

information last updated July 2006



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