Parkinson's disease; Nogo-A; neuronal transplantation; neuronal phenotype; neurotrophic factors; dopaminergic neurons; signal transduction
Di Santo Stefano, Seiler Stefanie, Ducray Angélique D., Widmer Hans Rudolf (2019), Conditioned medium from Endothelial Progenitor Cells promotes number of dopaminergic neurons and exerts neuroprotection in cultured ventral mesencephalic neuronal progenitor cells, in Brain Research
, 1720, 146330-146330.
Di Santo Stefano, Widmer HansR (2018), Neurotrophic factor-based strategies to enhance survival and differentiation of neural progenitor cells toward the dopaminergic phenotype, in Brain Circulation
, 4(3), 139-139.
Seiler Stefanie, Di Santo Stefano, Sahli Sebastian, Andereggen Lukas, Widmer Hans Rudolf (2017), Nogo-receptor 1 antagonization in combination with neurotrophin-4/5 is not superior to single factor treatment in promoting survival and morphological complexity of cultured dopaminergic neurons, in Brain Research
, 1668, 56-64.
Seiler Stefanie, Di Santo Stefano, Andereggen Lukas, Widmer Hans R. (2017), Antagonization of the Nogo-Receptor 1 Enhances Dopaminergic Fiber Outgrowth of Transplants in a Rat Model of Parkinson’s Disease, in Frontiers in Cellular Neuroscience
, 11, 151.
Perez-Bouza Alberto, Di Santo Stefano, Seiler Stefanie, Meyer Morten, Andereggen Lukas, Huber Alexander, Guzman Raphael, Widmer Hans R. (2017), Simultaneous transplantation of fetal ventral mesencephalic tissue and encapsulated genetically modified cells releasing GDNF in a hemi-parkinsonian rat model of Parkinson’s disease, in Cell Transplantation
Seiler S Di Santo S and Widmer HR (2016), Nogo-A neutralization improves graft function in a rat model of Parkinson’s disease, in Front. Cell. Neurosci
, 10:87, 1.
Seiler Stefanie, Di Santo Stefano, Widmer Hans Rudolf (2016), Non-canonical actions of Nogo-A and its receptors, in Biochem Pharmacol
, (100), 28-39.
Liechti R, Ducray AD, Jensen P, Di Santo S, Seiler S, Jensen CH, Meyer M, Widmer HR (2015), Characterization of FA1/dlk1 expressing cells in the rat nigrostriatal system and effects of a 6-OHDA lesion., in PLoS One.
, 10(2), e0116088.
Jensen P, Ducray AD, Widmer HR, Meyer M (2015), Effects of forskolin on Trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons, in Neuroscience
, 317, 699.
Jensen Pia, Heimberg Michel, Ducray Angelique D., Widmer Hans R., Meyer Morten (2015), Effects of forskolin on Trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons, in Neuroscience
, 25(3), 156-156.
Schawkat K, Di Santo S, Seiler S, Widmer HR (2015), Loss of Nogo-A expressing neurons in a rat model of Parkinson’s disease., in Neuroscience
Seiler Stefanie, Widmer Hans Rudolf (2015), Nogo-A and its functions beyond axonal inhibition: The controversial role of Nogo-A in Parkinsons’s disease, in Neural Regen Res
, 10(8), 1223.
Seiler Stefanie, Pollini Dario, Di Santo Stefano, Widmer Hans R. (2014), Antagonizing Nogo-receptor 1 promotes the number of cultured dopaminergic neurons and elongates their neurites, in NEUROREPORT
, 25(3), 160-160.
Di Santo Stefano, Seiler Stefanie, Fuchs Anna-Lena, Staudigl Jennifer, Widmer Hans Rudolf (2014), The Secretome of Endothelial Progenitor Cells Promotes Brain Endothelial Cell Activity through PI3-Kinase and MAP-Kinase, in PLOS ONE
, 9(4), e95731.
Jensen Pia, Heimberg Michel, Ducray Angelique D., Widmer Hans R., Meyer Morten (2014), Trefoil Factor 1 in the nigrostriatal system of 6-hydroxydopamine-lesioned rats, in NEUROREPORT
, 25(3), 156-156.
Maroof Asif M., Keros Sotirios, Tyson Jennifer A., Ying Shui-Wang, Ganat Yosif M., Merkle Florian T., Liu Becky, Goulburn Adam, Stanley Edouard G., Elefanty Andrew G., Widmer Hans Ruedi, Eggan Kevin, Goldstein Peter A., Anderson Stewart A., Studer Lorenz (2013), Directed Differentiation and Functional Maturation of Cortical Interneurons from Human Embryonic Stem Cells, in CELL STEM CELL
, 12(5), 559-572.
Jensen P., Heimberg M., Ducray A. D., Widmer H. R., Meyer M. (2013), Expression of Trefoil factor 1 in the developing and adult rat ventral mesencephalon.
, Cognizant Communication Corporation, NY, USA.
Jensen P., Heimberg M., Ducray A. D., Widmer H. R., Meyer M. (2012), Expression of Trefoil Factor 1 in the Nigrostriatal System of Hemiparkinsonian Rats Versus Unlesioned Controls
, Cognizant Communication Corporation, NY, USA.
Tokarska-Schlattner Malgorzata, Epand Raquel F., Meiler Flurina, Zandomeneghi Giorgia, Neumann Dietbert, Widmer Hans R., Meier Beat H., Epand Richard M., Saks Valdur, Wallimann Theo, Schlattner Uwe (2012), Phosphocreatine Interacts with Phospholipids, Affects Membrane Properties and Exerts Membrane-Protective Effects, in PLOS ONE
, 7(8), e43178.
1. BACKGROUNDParkinson's disease (PD) is a disabling neurodegenerative disorder of unknown etiology characterized by a predominant and progressive loss of dopaminergic (DAergic) neurons of midbrain. While medication therapy provides adequate alleviation of the symptoms for several years, the long term treatment is complicated by progressive disability and development of severe side effects. A therapeutic concept for long-term treatment of PD is the replacement of the degenerated dopaminergic neurons by transplanting cells releasing dopamine. Clinical experiences have revealed proof of principle but also demonstrated significant limitations which ask for optimization of protocols. The major problems for cell replacement strategies in PD are concerning the appropriate source of donor tissue, the poor survival of transplanted cells and the suboptimal DAergic innervation of the host striatum.2. WORKING HYPOTHESISRecent findings from our and other laboratories suggest that neuroprotective molecules and neurotrophic factors support the survival of neural dopaminergic cells and the engraftment of the transplant in the host brain. Accumulating evidence indicate that Nogo-A plays an essential role in modulating the processes of axonal growth and innervation. Therefore, the combination of the beneficial effects of neurotrophic factors, neuroprotective molecules and Nogo-A inhibition might open new scenarios for PD therapies. In the present research project we will explore if the transplantation approach based on intracerebral application of anti-Nogo-A antibodies and treatment with creatine and/or neurotrophins significantly ameliorate the outcome of current cell transplantations protocols in PD. 3. SPECIFIC AIMSAim I.Assessment of the expression pattern of Nogo-A and NgR1 in the nigrostriatal system of the rat brain during development and in the PD disease state.Aim II.Assessment of the effects of Nogo-A neutralization in fetal rat VM cultures and characterization of the interactions with neurotrophic factors.Aim III.Assessment of the effects of Nogo-A neutralization on VM GFP transplant function in the 6-OHDA rat model of PD. 4. EXPERIMENTAL DESIGN AND/OR METHODS Distribution of Nogo-A and NgR1 in the nigrostriatal system of rat and human brain will be assessed using immunohistochemistry. By means of in vitro models of PD the effects of Nogo-A neutralization will be assessed using immunohistochemistry followed by analyzes of morphology. HPLC will be used to measure levels of dopamine in cultures. Identification of interactions with neurotrophic factors and creatine will include Western blot analyzes, signal transduction assessments and PCR. Using the 6-OHDA rat model of PD, we will explore Nogo-A neutralization on VM GFP transplants function of rats by means of behavioral assessment, immunohistochemistry and Western blot analysis. Phenotype identification of surviving neurons in grafts with or without factor pretreatment will be studied in the same setting using immunohistochemical methods in combination with measures of dopamine levels in the host brain. The possible alterations of host brain cell proliferation and neurogenesis will similarly be investigated in the 6-OHDA rat model of PD by means of BrdU injections and histological analyses.5. EXPECTED VALUE OF THE PROPOSED PROJECTThe proposed experiments are expected to contribute to the development of improved strategies and to increase understanding of events after transplantation in cell replacement approaches in PD. They concern a highly actual field of neurotransplantation research. Relevance to our studies is furthermore given that the used antibodies are currently in clinical evaluation. The impact of our approach likewise holds up for neural transplantation using alternative tissue sources and to other CNS lesions.