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The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.
The present study deals with the topic how a town can use its cultural heritage or,
more precisely, its industrial culture as a means to market itself as an innovative
business location and to foster a more pronounced sense of civic cohesion among
residents. Economic theory suggests that, nowadays, traditional location factors
such as access to resources and a performant infrastructure are less important than
in the industrial age. Recently, factors like a city’s potential to generate and retain
human and creative capital have emerged. Accordingly, the economic and social
role of cities has shifted – from a place where workers lived and manufactured
goods towards a deeply interwoven ecosystem of knowledge-intense value creation.
The question at the root of the present study is how Heidenheim’s rich industrial
cultural heritage can be used as a future-pointing source of power for rebranding
the town. This rebranding concept has to be developed according to the town’s role
in past, present and future, thus creating actual economic and societal value.
Industrial culture bears branding potential and is closely related to various aspects
of modern life and work. The study examines possibilities to create awareness for
these relations connecting past, present and future. Their relevance shall be
emphasized in order to establish both points of orientation and authenticity of place
in times when macroeconomic and societal trends are difficult to predict. Ideally,
residents shall be given a sort of local identification to hold on to, and potential
investors and entrepreneurs shall be encouraged to sustainably experience the
innovation-based DNA of Heidenheim. Therefore, the study searches for a value
proposition that takes into account the points mentioned above on terms of an
innovative theoretic framework. As a result of this thesis, precise suggestions for
the implementation of a new branding strategy based on the conceptual guidelines
developed in this study will be proposed to the municipality of Heidenheim and, in
addition, an interface using principles of virtual and augmented reality will be
introduced.