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@PHDTHESIS{vanMaarschalkerweerd:206202,
      author       = {van Maarschalkerweerd, Andreas},
      title        = {{S}tructural and biophysical characterization of
                      $\alpha$-synuclein and itsinteraction with lipid membranes},
      school       = {University of Copenhagen},
      type         = {Dr.},
      reportid     = {PUBDB-2015-00716},
      pages        = {-},
      year         = {2014},
      note         = {Post referee full text in progress.; University of
                      Copenhagen, Diss., 2014},
      abstract     = {Parkinson's disease (PD) is a pervasive neurodegenerative
                      disorder affecting millions of lives worldwide. There is
                      currently no cure for PD and the pharmacological treatment
                      is hence only symptomatic. Despite immense scientific
                      efforts, there is still a lack of basic understanding of the
                      pathogenesis of PD. Such understanding might be the key to
                      optimized drug discovery strategies. Due to the outspoken
                      similarities between PD and a number of other
                      neurodegenerative and amyloid diseases, an enhanced
                      understanding of PD is potentially also of general
                      interest.PD is hallmarked by the presence of lipid-rich
                      protein inclusions in the brain called Lewy Bodies (LB). LB
                      are characterized by a high content of the
                      $\alpha$-synuclein ($\alpha$SN) protein. A number of
                      familiar point mutations within $\alpha$SN have been shown
                      to cause early-onset genetic PD. The native structure of
                      αSN is generally believed to be intrinsically disordered.
                      However, within LB $\alpha$SN is found as elongated
                      aggregates (amyloid fibrils) characterized by cross-$\beta$
                      structure. The fibrillated $\alpha$SN found in LB is
                      believed to be an inert reservoir. The cytotoxic effect of
                      $\alpha$SN is allegedly associated with the occurrence of
                      transient oligomer structures that form prior to the
                      formation of amyloid fibrils. Several studies have sought to
                      elucidate on the molecular mechanism of $\alpha$SN
                      interaction with lipid membranes in relation to the apparent
                      cytotoxicity of oligomeric $\alpha$SN.This thesis presents
                      experimental work addressing the structure of $\alpha$SN,
                      aspects of $\alpha$SN-membrane interaction and process
                      behind $\alpha$SN mutant fibrillation. The primary
                      experimental methods are small-angle X-ray scattering (SAXS)
                      and fluorescence spectroscopy with emphasis on the
                      environmental sensitive dye Laurdan.During purification of
                      $\alpha$SN we observed an unexpected chromatographic
                      feature. This feature was revealed to be a consequence of
                      the formation of partly compacted covalent αSN dimers as
                      shown by e.g. SAXS and mass spectroscopy. Two projects were
                      performed on the interactions of $\alpha$SN and lipid
                      membranes. Here we showed that $\alpha$SN is able to
                      dehydrate anionic membranes and to induce lysis of liposomes
                      associated with the formation of $\alpha$-helical rich
                      $\alpha$SN-lipid co-aggregates. Additionally we showed that
                      cholesterol could modulate the interaction between
                      $\alpha$SN oligomers and otherwise inert neutral lipid
                      membranes. Finally a SAXS based study was conducted on the
                      fibrillation of $\alpha$SN E46K mutant proving that the
                      fibrillation of E46K is significantly different from that of
                      wild-type $\alpha$SN under the applied conditions.},
      keywords     = {Dissertation (GND)},
      cin          = {EMBL-User},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {DORIS Beamline D1.2 (POF2-54G13) / PETRA Beamline P12
                      (POF2-54G14)},
      pid          = {G:(DE-H253)POF2-D1.2-20130405 /
                      G:(DE-H253)POF2-P12-20130405},
      experiment   = {EXP:(DE-H253)D-D1.2-20150101 / EXP:(DE-H253)P-P12-20150101},
      typ          = {PUB:(DE-HGF)11},
      url          = {https://bib-pubdb1.desy.de/record/206202},
}