Crossseads

This proposal is based on the hypothesis that a number of brain disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) share common pathogenic mechanisms leading to neurodegeneration. A traditional view on these devastating disorders focuses on individual, disease-specific enzymes and/or aggregating proteins contributing to aspects of neuropathology. Here, we combine experimental approaches from fundamental, pre-clinical and clinical neuroscience with computational approaches to identify cross-disease pathways leading to pathogenic protein aggregation. All three clinical conditions addressed have at least one feature in common: aggregation of pathogenic proteins associated with neurodegeneration. For example, Abeta peptides modified by glutaminyl cyclase (QC) to form pyroglutamate (pGlu) act as seed for protein aggregation and provoke neurodegeneration in AD. We have recently demonstrated that pGlu-Abeta is also present in Lewy bodies of substantia nigra dopaminergic neurons of PD subjects and induces cross-seeding of a-synuclein. We intend to address 4 specific Aims: (1) We will use biochemical, biophysical, cell biological and molecular biological methods to characterize the cross-seeding of pGlu-Abeta, a-synuclein and huntingtin peptides in vitro. (2) We will investigate the co-occurrence of these peptides in brain structures affected in AD (nucleus basalis Meynert, neocortex, hippocampus), PD (substantia nigra) and HD (basal ganglia, globus pallidus, extended amygdala) and in animal models thereof. (3) We will generate a map of pathogenic protein (co)-aggregates in human brain and respective animal models and develop a computer-based model of neuronal circuits affected by such protein aggregates in individual clinical conditions. This map will be uploaded to an open access public database that allows comments, correction and addition of data from others. (4) We will interfere with pathogenic protein aggregation by vaccination against disease-related epitopes in animal models to delineate novel therapeutic strategies. Collectively, experts in the fields of AD (Roßner), PD (Hunot), HD (von Hörsten), computational network analyses (Bjaalie) and preclinical development (Demuth) will join forces to analyse pathophysiological mechanisms across clinical disease boundaries. This approach will add significant value to current knowledge and will open novel therapeutic windows for treatment of the disorders addressed. (2) The project's relevance for the aims of the call A) Relevance to the aims of the call. The present proposal is highly relevant and fully addresses overall goals of the JPND Programme and the specific aims of the call, by studying cross-seeding of pathogenic proteins in three clinical conditions of the highly prevalent neurodegenerative disorders, AD, PD and HD. B) Innovation potential of the project. The molecular triggers for neurodegeneration and for pathological protein aggregation in neurodegenerative diseases are largely unknown. This proposal is planned to test the hypothesis that post-translational modifications such as QC-catalysed pGlu-formation induce or enhance the amyloidogenic properties of Abeta, a-synuclein and huntingtin. Moreover, applicants want to address the cross-seeding capacity of disease-related peptides (pGlu-Abeta in AD, a-synuclein in PD, huntingtin in HD). This hypothesis is based on strong preliminary data. The experimental design is well-founded and is likely to generate comprehensive information. C) Impact of the expected results on the scientific community and the field of research. Strategies to reduce the abundance of protein aggregates might be a suitable approach to develop causal therapies against neurodegenerative diseases. The expected results will be of tremendous value for further basic and clinical research and for the develoment of novel therapeutic strategies to treat the diseases addressed. Results will be