Research Report 2010 - MDC

Erich E. WankerStructure of the GroupGroup LeaderProf. Dr. Erich WankerScientistsDr. Vinayagam ArunachalamDr. Tachu BabilaRaphaele FoulleDr. Ralf Friedrich*Christian HänigDr. Maciej Lalowski*Dr. Katja Neugebauer*Dr. Albrecht Otto*Dr. Christine Petersen*Dr. Spyros Petrakis*Proteomics and Molecular Mechanismsof Neurodegenerative DisordersProteins are central to almost all cellular functions, such as metabolism, regulation of cellgrowth and communication between cells. They are synthesized from amino acid buildingblocks and must fold into unique three-dimensional structures in order to become functionallyactive. Misfolded proteins are a normal feature of this process. Under physiological conditionsmisfolded proteins are efficiently degraded. When cells are challenged with environmentalstress or genetic mutations, however, protein misfolding increases dramatically and changesvarious cascades of cellular function, which leads to the manifestation of pathologicalphenotypes. More than 35 systemic and neurological diseases are caused by the formation ofabnormally folded protein species, among them the late-onset neurodegenerative disordersAlzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). To date, onlysymptomatic treatments with limited effectiveness are available for these illnesses.The main objective of our work is to elucidate themolecular mechanisms of protein misfolding diseases.Several lines of experimental evidence indicate thatabnormal protein assembly in vitro and in vivo is a multistepprocess, involving the formation of on- and offpathwayaggregation intermediates such as sphericaloligomers or worm-like protofibrils. However, the structure,size and morphology of these potentially highlytoxic structures have not been fully clarified. Moreover,it remains unclear how misfolded protein species interactwith their cellular environment and cause cellulardysfunction and toxicity. Evidence was presentedrecently that abnormal protein aggregates alter thefunction of complex cellular processes such as membranesignaling or protein degradation mediated by theubiquitin proteasome system (UPS). However, theimpact of these changes on cell function remains largelyunknown. Also, it remains unclear why certain typesof cells accumulate misfolded proteins while others donot.Chemical compounds that are able to modulate proteinmisfolding pathways in vitro and in vivo are highly valuabletools to analyze the complex protein assemblyprocess. They are valuable starting points for therapydevelopment. Besides small molecules we are alsohighly interested in finding proteins or peptides thatdirectly influence the amyloid formation cascade. Theyare identified using high throughput protein interactiontechnologies such as an automated yeast twohybrid(Y2H) system. Recently, a network of dysregulatedprotein-protein interactions (PPIs) for HD was createdusing bioinformatic strategies. This study allowedthe identification of the neuron-specific protein CRMP1,a protein that dramatically influences polyglutamine(polyQ)-mediated huntingtin aggregation in cell-freeand in vivo disease model systems.Finally, we aim to develop innovative technologies anddatabases for systematic proteomics research. An interactomedatabase termed UniHI was established at theMDC that contains more than 250,000 human interactionsand allows scientists to link individual proteins toing cascades and disease processes.182 Function and Dysfunction of the Nervous System