The Goldberg Lab is focused on discovering the molecular pathways that lead to Parkinson’s disease (PD), which afflicts more people than any other neurodegenerative movement disorder. PD is characterized by the progressive loss of pigmented neurons, primarily within the substantia nigra, which project to the striatum and release dopamine. Severe loss of dopaminergic neurons causes bradykinesia (slowness of movement), rigidity, resting tremor and postural instability. Despite intensive research, the cause of PD remains a major unsolved mystery. We have recently made important progress by developing mice bearing loss-of-function mutations in the Parkin and DJ-1 genes linked to inherited forms of PD. Very little is known about the cellular functions of the proteins encoded by these genes. Therefore, modeling these mutations in mice is vital for advancing our basic understanding of biology as well as PD pathogenesis.
Our studies of parkin knockout mice have provided valuable clues to the molecular mechanisms by which Parkin mutations cause PD (Goldberg et al., 2003). Parkin knockout mice have abnormal dopamine regulation as well as electrophysiological and motor dysfunctions involving the nigrostriatal circuit (Goldberg et al., 2003). Our proteomic analysis identified the proteins most altered in the ventral midbrain of Parkin knockout mice, most of which have either mitochondrial or antioxidant functions. This led to our discovery of mitochondrial dysfunctions and increased protein and lipid oxidation in parkin knockout mice (Palacino et al., 2004). Using DJ-1 knockout mice, we have discovered novel and important roles for DJ-1 in dopamine-mediated neuronal activity and locomotor behavior (Goldberg et al., 2005). We have already discovered ways to pharmacologically rescue some of the defects in DJ-1 knockout mice, specifically by administration of D2-type dopamine receptor agonists.
Future research will focus on discovering the in vivo function of these proteins by using innovative genetic, biochemical, and cell biological tools. The ultimate goal is to gain sufficient understanding through the analysis of genetic PD models to develop and test novel therapeutic and preventative treatments. Given the genetic evidence that many more genes will be identified with mutations that cause familial PD, we will capitalize on these imminent genetic breakthroughs by generating and analyzing additional mice that bear newly identified mutations.
Studying these mutations in mice holds great promise for identifying and eventually repairing the molecular pathways that lead to Parkinsonism. These mice will serve as tools to translate breakthroughs in human PD genetics into major advances in our understanding of basic neuroscience and PD pathogenesis.
Rosen K. M., Veereshwarayya V., Moussa C. E-H., Fu Q., Goldberg MS, Schlossmacher M. G., Shen J., Querfurth H. W., Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells, (2006) Journal of Biological Chemistry, 281, 12809-12816.
Goldberg MS, Pisani P., Haburcak M., Vortherms T. A., Kitada T., Costa C., Tong Y., Martella G., Tscherter A., Martins A., Bernardi G., Roth B. L., Pothos E. N., Calabresi P., Shen J., Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1, (2005) Neuron, 45, 489-496.
*Palacino J. J., *Sagi D., *Goldberg MS, Krauss S., Motz C., Klose J., Shen J., Mitochondrial dysfunction and oxidative damage in Parkin-deficient mice, (2004) Journal of Biological Chemistry, 279, 18614-18622.
Goldberg MS, Fleming S. M., Palacino J. J., Cepeda C., Lam H. A, Bhatnagar A., Meloni E. G., Wu N., Ackerson L. C., Klapstein G. J., Gajendiran M., Roth B. L., Chesselet M-F, Maidment N. T., Levine MS, Shen J., Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons, (2003) Journal of Biological Chemistry, 278, 43628-43635.
Fujiwara H., Hasegawa M., Dohmae N., Kawashima A., Masliah E., Goldberg MS, Shen J., Takio K., Iwatsubo T., Alpha-synuclein is phosphorylated in synucleinopathy lesions, (2002) Nature Cell Biology, 4, 160-164.
Sharon R., Goldberg MS, Bar-Josef I., Betensky R. A., Shen J., Selkoe D. J., a-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins, (2001) Proceedings of the National Academy of Sciences, 98, 9110-9115.
Goldberg MS & Lansbury PT Jr., Is there a cause and effect relationship between a-synuclein fibrillization and Parkinson’s disease?, (2000) Nature Cell Biology, 2, E115-119.