A unifying molecular event in neurodegenerative disorders is aberrant self-assembly of proteins into amyloid fibers with a hallmark cross-β-sheet arrangement. Parkinson’s disease (PD) is the second most common neurodegenerative disorder (after Alzheimer’s disease) and the most common movement disorder. PD is characterized by widespread deterioration of subcortical structures of the brain, especially dopaminergic neurons in the substantia nigra1. Conformational changes resulting in assembly of the intrinsically-unstructured protein α-synuclein (αS) into amyloid fibers is directly related to PD2,3. The exact function of αS is unknown, but it is suggested to be involved in synaptic-vesicle release and trafficking, regulation of enzymes and transporters, and control of the neuronal apoptotic response4,5. αS is present at presynaptic nerve terminals6,7,8 and, intriguingly, also in many cells outside the brain. Of importance for initiation and spreading of PD, it was shown recently that αS is expressed in enteroendocrine cells of the gut epithelium; these cells directly connect to αS-containing nerves and thus form a neural circuit from the gut to the brain9.

αS assembles via oligomeric intermediates to amyloid fibrils under pathological conditions10. Although soluble αS oligomers have been proposed to be toxic11,12, work with pre-formed αS fibrils have demonstrated that the amyloid fibrils themselves are toxic and can be transmitted from cell to cell and are also able to cross the blood-brain barrier13,14,15. Many synthetic as well as naturally-occurring small molecules can modulate αS amyloid formation in vitro and cross-reactivity with other amyloidogenic proteins have been demonstrated, e.g., amyloid-β in Alzheimer’s and amylin in type-2 diabetes16. It was recently speculated that the gut microbiome can modulate PD progression17 and bacterial proteins affect αS amyloid formation in vitro18.

Despite the initial association of amyloids with proteins involved in neurodegenerative disorders, an increasing number of proteins from all kingdoms of life have been reported to form functional as well as pathological amyloids19. For example, biofilms are structures used by bacteria to adhere to surfaces which contain amyloids in the form of curli20,21. In humans, amyloids of the protein Pmel17 template and accelerate covalent polymerization of reactive small molecules into the pigment melanin and the factor XII protein of the hemostatic system is activated by amyloid formation22. Recently, it was revealed that food allergens may adopt amyloid states in order to survive the harsh conditions during the gastrointestinal transit. This phenomenon has been reported for allergenic proteins in various food, such as β-lactoglobulin, caseins, ovalbumin, lysozyme, and β-parvalbumin23. For β-parvalbumin, it was deduced that the low pH in the gut triggered calcium ion release and the resulting apo-protein then assembled into amyloids. Moreover, an amyloidogenic state of β-parvalbumin was necessary for its ability to bind immunoglobulin E (IgE) and trigger hypersensitivity in the host23,24. Thus, the amyloid state may play a distinct function in epitope presentation of proteins causing allergies.

Fish β-parvalbumins represent the major allergen in fish hypersensitive patients and are small, calcium-binding proteins with three EF-hand motifs of which one is non-functional20,21,25. Most fish species are rich in β-parvalbumins with about 0.2 g of such protein per 100 g muscle tissue26. This protein has been evaluated as a compliance marker for fish intake in human diet interventions and epidemiological studies since humans express mostly another isoform, α-parvalbumin27. Despite triggering allergies in a fraction of the population, fish is considered beneficial against several age-related diseases such as cardiovascular disease28,29 as well as dementia and Alzheimer’s disease30. Favorable effects are popularly ascribed to omega-3 fatty acids31, but direct evidence is lacking32 and thus other fish components may as well be responsible.

Because human amyloidogenic proteins can cross-react, one may speculate that fish β-parvalbumin may have ability to interact with human amyloidogenic proteins. Because the protein is highly abundant in fish and transverse to the host blood upon eating fish, this becomes a relevant question. To test this hypothesis, we here probed the putative cross-talk between Atlantic cod β-parvalbumin (Gad m 1), here abbreviated PV, and human αS using a battery of biophysical methods. This particular β-parvalbumin was previously shown to adopt a highly-stable amyloid state in the absence of calcium ions (Ca) that was recognized by human serum IgE more strongly than the monomer23,24. Our cross-reactivity experiments in vitro presented here demonstrate that PV amyloids block αS amyloid formation via a mechanism that involves binding of αS monomers to the PV amyloids. Thus, we speculate that fish intake may provide health benefits through PV amyloid interactions that prevent neurodegenerative processes.