Gallardo R, Ramakers M, De Smet F, Claes F, Khodaparast L, Khodaparast L, Couceiro JR, Langenberg T, Siemons M, Nyström S, Young LJ, Laine RF, Young L, Radaelli E, Benilova I, Kumar M, Staes A, Desager M, Beerens M, Vandervoort P, Luttun A, Gevaert K, Bormans G, Dewerchin M, Van Eldere J, Carmeliet P, Vande Velde G, Verfaillie C, Kaminski CF, De Strooper B, Hammarström P, Nilsson KP, Serpell L, Schymkowitz J, Rousseau F. De novo design of a biologically active amyloid. Science. 2016 Nov 11;354(6313) PubMed.
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Drexel University
This paper reports on several important findings derived from a carefully designed study on the VEGFR2 protein. Unlike Aβ-protein or α-synuclein, VEGFR2 does not aggregate in vivo under normal or pathogenic conditions. However, VEGFR2 can be induced to aggregate via an interaction with a de novo designed peptide, referred to as a vascin. The sequence of vascin was derived from a specific VEGFR2 fragment, which was predicted to have amyloidogenic properties and is at the same time homologous to VEGFR2, which allows it to seed its aggregation in a selective way, i.e., without seeding the aggregation of other proteins.
VEGFR2 was selected for this study because it has a well-defined physiological function associated with specific cells. As vascin is introduced into these specific cells, it causes VEGFR2 to aggregate, therefore inhibiting the ability of VEGFR2 to perform its normal function. This appears to be the source of VEGFR2 aggregation-induced toxicity in these specific cells, for which the normal function of VEGFR2 is essential. However, VEGFR2 aggregation in other types of cells does not cause toxicity as those other cells do not depend on the normal function of VEGFR2, which implies that VEGFR2 aggregates are not particularly toxic on their own.
It is likely that other proteins that do not aggregate under normal or pathological conditions could be induced to aggregate through seeding by a de novo designed peptide that is homologous to the original protein. As in the case of VEGFR2, this induced aggregation could lead to a loss-of-function induced toxicity in those cells, for which the protein function is of essence. This is definitely a very important discovery, as it provides a way to control specific protein function by manipulating protein aggregation.
Proteins associated with neurodegenerative diseases, such as Aβ-protein, α-synuclein, tau, and others, on the other hand, are aggregation-prone, at least under pathological conditions, but perhaps also under normal conditions, which makes them different from VEGFR2. Moreover, their physiological role is still not completely understood. For example, evidence is emerging that Aβ is an antimicrobial and antiviral protein (the associated Alzforum story was posted online several months ago). If the normal function of Aβ in vivo is to act mainly as an immune defense against microbes and viruses, then Aβ aggregation must occur under non-AD conditions. A loss of function would lead to an increase of microbial and viral infections, but would not necessarily lead to a massive neuronal loss observed in AD.
Thus, there is to date no convincing evidence that AD is a consequence of a loss of function of Aβ. However, there is a correlation between neuronal loss and aberrant aggregation of tau into neurofibrillary tangles. Tau has an important physiological function, which is lost when tau aggregates into neurofibrillary tangles in AD. However, the molecular basis of AD is multifaceted and the exact molecular mechanisms underlying the pathology are not well understood, so it is too early to speculate as to which extent the findings of this study may be applicable to neurodegenerative diseases.
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