CrossSeeds: Mechanisms of pathogenic protein cross-seeding in neurodegenerative disorders

The CrossSeeds project addresses the hypothesis of common pathogenic mechanisms occurring in Alzheimer's disease, Parkinson's disease, and Huntington's disease. It is known that beta-amyloid, alpha-synuclein and the protein huntingtin are aggregating in Alzheimer?s, Parkinson?s and Huntington?s disease respectively. We can report new findings regarding the formation of pathogenic protein fibrils of the three types and an acceleration of fibril formation in co-aggregation studies between Abeta, huntingtin forms and alpha-synuclein protein. The highest toxicity was detected for extracellular exposure to oligomeric ?-synuclein/pGlu-Abeta mixtures. New antibodies have been generated against pyro-glutamate (pGlu) modified peptides. We were able to observe co-localization of aggregates consisting of Abeta, huntingtin and alpha-synuclein peptide derivate in vivo in several disease models, comforting the hypothesis that pyro-glutamate modification of peptides had a central role in these diseases. Behavior studies on the animal models showed motor dysfunctions, emotionality, cognitive deficits, thereby validating the models. We have completed the brain-wide mapping of pathogenic aggregates in all models and all brain sections have been registered to 3D reference atlases (Waxholm rat brain atlas and Allen mouse brain atlas). This data is made available through a shared database. Further, we have developed a workflow and new software tools for a region-wise analysis of the image data collected and have results on the AD mouse and AD rat. After anchoring to the reference atlas, the images are segmented and the number of amyloid plaques is quantified. The outcome consist of coordinate-based analysis of pathogenic proteins aggregates. This database allows for future scientific results of individual research groups on pathogenic protein aggregation to be put in context with each other to achieve an unprecedented gain of knowledge on cross-disease mechanisms of pathogenic protein deposition thereby contributing to reuse of data according to the FAIR principles.

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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. 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 alpha-synuclein. We will 1) use biochemical, biophysical, cell biological and molecular biological methods to characterize the cross-seeding of pGlu-Abeta, alpha-synuclein and huntingtin peptides in vitro, (2) investigate the co-occurrence of these peptides in brain structures affected in AD, PD, and HD, (3) 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, and (4) interfere with pathogenic protein aggregation by vaccination against disease-related epitopes in animal models to delineate novel therapeutic strategies. Experts in the fields of AD, PD, HD, computational network analyses, and preclinical development 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.