Nordic Molecular Medicine Network (NMMN) Meeting Oslo 2013

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Cristine Betzer - Speaker

The beauty and the beast - alpha-synuclein in health and disease The Neurodegenerative Disease Laboratory, Danish Research Institute of Translational Neuroscience, Department of Biomedicine, Aarhus University Poul Henning Jensen, Jette Bank Lauridsen, Cristine Betzer, Louise Berkhoudt Lassen, Jin Zheng, Rikke Hahn Kofoed, Lærke Dalsgaard Nielsen -synuclein is a small intracellular protein most abundantly expressed in nerve terminals of the central nervous system. It exhibits various roles but most importantly functions as an essential chaperone maintaining the fidelity of the SNARE machinery governing the synaptic vesicular fusion process. -synuclein is closely linked to neurodegenerative diseases, so-called synucleinopathies. Rare missense mutations and gene multiplications of -synuclein causes autosomal dominant Parkinson disease (PD) and Dementia with Lewy bodies (DLB) leading to accumulation of aggregated -synuclein in degenerating brain cells. In common sporadic PD and DLB, like in the familial cases, does -synuclein aggregate in neurons and aggregation in oligodendrocytes occurs in multiple systems atrophy. Phosphorylation of -synuclein serine 129 is a hallmark of the pathological cellular aggregates. Differerent factors affect the aggregation of -synuclein, e.g. the protein, p25, which stimulates aggregation. Clinical research suggests that synucleinopathies are progressive disorders wherein increasing parts of the brain develop -synuclein aggregates and cell loss. Recent rodent models are able to recapitulate this process of intracellular aggregation, externalization, transcellular spreading and repeated aggregation after a single injection of in-vitro formed -synuclein aggregates. Our group investigates various aspects of -synuclein biology, partly based on screenings for 1) ligands for normal monomer and abnormal aggregated -synuclein, 2) genes expressed in cells subjected to -synuclein aggregate stress 3) kinase inhibitors modulating -synuclein cellular stress. Different pathways are studied in cell lines, primary brain cell cultures and transgenic animal models. The Dandrite project focuses on signaling by misfolded -synuclein and protective cellular mechanisms: Cytotoxic and protective phosphorylation pathways, NF-kB signaling and calcium regulatory pathways upon -synuclein induced stress. The biology of spreading is studied at the discrete steps of -synuclein misfolding, excretion, uptake and templating of misfolding. Moreover, novel transgenic mice models are characterized and developed that aims at modulating -synuclein metabolism, e.g. conditional p25α expressors and by inoculation of -synuclein aggregates.
17 Sep 201319 Sep 2013


ConferenceNordic Molecular Medicine Network (NMMN) Meeting Oslo 2013

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