Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases

A range of human degenerative conditions, including Alzheimer's disease, light-chain amyloidosis and the spongiform encephalopathies, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils or plaques. It has been shown previously that fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3'-kinase and the amino-terminal domain of the Escherichia coli HypF protein. Here we show that species formed early in the aggregation of these non-disease-associated proteins can be inherently highly cytotoxic. This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.     

Identification and electroantennographic activity of sex-specific geranyl esters in an abdominal gland of femaleAgriotes obscurus (L.) andA. lineatus (L.) (Coleoptera,Elateridae)

Summary Both geranyl hexanoate and geranyl octanoate were identified by GC/MS as the major volatiles in a hitherto uncharacterized abdominal gland in females inAgriotes obscurus. Only geranyl octanoate was found inA. lineatus. In EAG tests performed onA. obscurus males, geranyl butanoate and geranyl hexanoate elicited the strongest antennal responses.Financial assistance was donated by The Bank of Sweden Tercentenary Foundation and the Axel and Margaret Ax: son Johnson Foundation. We thank B Baur for statistical advice.     

Chemical space and biology

Chemical space--which encompasses all possible small organic molecules, including those present in biological systems--is vast. So vast, in fact, that so far only a tiny fraction of it has been explored. Nevertheless, these explorations have greatly enhanced our understanding of biology, and have led to the development of many of today's drugs. The discovery of new bioactive molecules, facilitated by a deeper understanding of the nature of the regions of chemical space that are relevant to biology, will advance our knowledge of biological processes and lead to new strategies to treat disease.     

Protein folding and misfolding

The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu. Folding and unfolding are crucial ways of regulating biological activity and targeting proteins to different cellular locations. Aggregation of misfolded proteins that escape the cellular quality-control mechanisms is a common feature of a wide range of highly debilitating and increasingly prevalent diseases.