The primary objective is to elucidate the functional role of GM1 ganglioside in the nuclear membrane during the course of neuronal differentiation. Expression of GM1 in this membrane increases markedly during the process outgrowth phase of differentiation and is seen as a potential functional determinant. This discovery was first made with neuroblastoma cells, (which will be used for much of the proposed study), and subsequently with primary neuronal cultures. In studies with neuroblastoma cells it would appear that only those neuritogenic procedures that induce sustained neurite outgrowth (i.e. terminal differentiation) can trigger upregulation of GM1 in the nuclear envelope and we hypothesize that such up regulation in the nuclear membrane is a general feature of process outgrowth. Since such events are characterized by enhanced influx of extracellular calcium into the cytosol, and apparently into the nucleus as well, the applicants further hypothesize that one of the functions of GM1 in the nuclear membrane is to regulate calcium flux in the nucleus during that critical period. The phenomenon of nuclear GM1 will be explored by seeking answers to the following questions: (a) How does the structure of nuclear envelope GM1 compare to that in the plasma membrane?; (b) Which portion of the nuclear envelope contains the GM1: inner membrane, outer membrane, and/or nuclear pore complex?; (c) Does nuclear GM1 have a role in modulation of calcium flux, as it does in the plasma membrane?; (d) Using combined biochemical and cytochemical assays applied to several neuroblastoma systems which either do or do not extend stable neurites, can we establish a correlation between GM1 upregulation in the nuclear membrane and commitment to terminal differentiation? (e) Using primary neuronal cultures and tissues sections of brain and PNS, can we demonstrate upregulation of nuclear GM1 as a general aspect of process outgrowth in the nervous system? (f) Does this upregulation of nuclear GM1 persist into maturity, or is it a specific feature of development? (g) What is the behavior of nuclear GM1 during regeneration?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-NEUC (01))
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Spinella, Giovanna M
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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Wu, Gusheng; Lu, Zi-Hua; André, Sabine et al. (2016) Functional interplay between ganglioside GM1 and cross-linking galectin-1 induces axon-like neuritogenesis via integrin-based signaling and TRPC5-dependent Ca(2+) influx. J Neurochem 136:550-63
Hadaczek, Piotr; Wu, Gusheng; Sharma, Nitasha et al. (2015) GDNF signaling implemented by GM1 ganglioside; failure in Parkinson's disease and GM1-deficient murine model. Exp Neurol 263:177-89
Wu, Gusheng; Lu, Zi-Hua; Kulkarni, Neil et al. (2012) Deficiency of ganglioside GM1 correlates with Parkinson's disease in mice and humans. J Neurosci Res 90:1997-2008
Ledeen, Robert; Wu, Gusheng (2011) New findings on nuclear gangliosides: overview on metabolism and function. J Neurochem 116:714-20
Wu, Gusheng; Lu, Zi-Hua; Kulkarni, Neil et al. (2011) Mice lacking major brain gangliosides develop parkinsonism. Neurochem Res 36:1706-14
Wu, Gusheng; Xie, Xin; Lu, Zi-Hua et al. (2009) Sodium-calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum. Proc Natl Acad Sci U S A 106:10829-34
Wang, Jianfeng; Lu, Zi-Hua; Gabius, Hans-Joachim et al. (2009) Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis. J Immunol 182:4036-45
Wang, Jianfeng; Wu, Gusheng; Miyagi, Taeko et al. (2009) Sialidase occurs in both membranes of the nuclear envelope and hydrolyzes endogenous GD1a. J Neurochem 111:547-54
Ledeen, Robert W; Wu, Gusheng (2008) Nuclear sphingolipids: metabolism and signaling. J Lipid Res 49:1176-86
Ledeen, Robert; Wu, Gusheng (2007) GM1 in the nuclear envelope regulates nuclear calcium through association with a nuclear sodium-calcium exchanger. J Neurochem 103 Suppl 1:126-34

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