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The Crossbeta Pathway

Protein Misfolding
Proteins are the building blocks of organisms and they carry out all biological processes. Humans have more then 30.000 different proteins, each with a specific function. For a protein to be able to exert its biological function, it needs to be correctly shaped (“folded” in biological terms) in a unique three-dimensional form. However, eventually, all proteins loose this unique shape (i.e. become “misfolded”) at some point in time, aggregate and hence loose their biological function. Damage to the shape of proteins occurs faster under conditions of stress, such as increase in temperature, contact to non-biological environments or elevated levels of glucose. Under normal circumstances, these obsolete proteins will effectively be recognized and subsequently removed from the body before causing any harm. If not they may become detrimental to the host and cause or contribute to highly debilitating diseases, such as atherosclerosis and Alzheimer’s disease.

Crossbeta
The term crossbeta indicates a specific ordering of misfolded proteins found in amyloid. Amyloid is a fibrillar form of aggregates of misfolded proteins that accumulate in a specific set of misfolding diseases called amyloidosis. In amyloid individual beta-strands of a beta-sheet run perpendicular to the fibril axis.

Crossbeta Pathway
Any protein, irrespective of its length and amino acid sequence is prone to misfolding, which can then results in the formation of a toxic and disease-associated amyloid-like crossbeta structure conformation. However, how misfolded proteins in the extracellular environment are recognized and cleared was unknown. We discovered and identified a class of proteins that specifically interacts with misfolded proteins and which promote the destruction of unwanted or damaging proteins. This newly identified Pathway is regarded as an efficient tuning mechanism preventing the onset of diseases that result from the accumulation of misfolded proteins. However, upon aging when more misfolded proteins stack in the body, the system will increasingly not be able to remove them adequately. Consequently, these misfolded proteins accumulate and contribute to the progression of a disease. Certain risk factors, either inherited or environmental, such as smoking, diabetes, infection or stress can enhance protein misfolding. Therapeutic modulation of the Pathway is as a new and effective manner to conquer a wide variety of diseases. Based on the crossbeta pathway Crossbeta Biosciences develops a product portfolio for the development of therapeutics for diseases associated with protein misfolding.