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.
Sotiriou S, Gibney G, Andreas D. Baxevanis AD and Nussbaum RL. A single nucleotide polymorphism in the 3'UTR of the SNCA gene encoding alpha-synuclein is a new potential susceptibilitylocus for Parkinson disease. Neuroscience Letters, 461(2):196-201, 2009.
KuoY-M, Li Z Jiao, GaboritN, Pan AK, OrrisonBM, BruneauBG, GiassonBI, SmeyneRJ, GershonMD and Nussbaum RL. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated a-synuclein gene mutations precede central nervous system changes. Hum Molec Genet, 19(9):1633-50, 2010.
Bernard DJ and Nussbaum RL. X-inactivation analysis of embryonic lethality in Ocrlwt-/-;Inpp5b-/-mice. Mammalian Genome: Volume 21, p. 186, 2010.
Corpe CP, Tu H, Eck P, Wang J, Faulhaber-Walter R, Schnermann J, Margolis S, Padayatty S, Sun H, Wang Y, Nussbaum RL, Espey MG, Levine M. Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. J Clin Invest 120: 1069-83, 2010.
Bothwell SP, Farber LW, Hoagland A, Nussbaum RL. Species-specific difference in expression and splice-site choice in Inpp5b, an inositol polyphosphate 5-phosphatase paralogous to the enzyme deficient in Lowe Syndrome. Mamm Genome: 21: 458-463, 2010.
Bothwell, SP, Chan, E, Bernardini IM, Kuo, YM, Gahl WA and Nussbaum RL. Mouse Model for Lowe Syndrome/Dent Disease 2 Renal Tubulopathy. J American Soc Nephrol, 22: 443-448, 2011.
Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B,Wakabayashi J, Sesaki H, Cheng Y, Finkbeiner S, Nussbaum RL, Masliah E, Edwards RH. Direct membrane associationdrives mitochondrial fission by the Parkinson Disease-associated protein a-synuclein. J Biol Chem 286(23):20710-26, 2011.