The Role of Misfolded Proteins in Neurodegenerative Diseases

Abstract

It has become increasingly apparent that there are a number of diseases which, although they have very different symptoms and aetiologies, may have in common a perturbation of protein folding. Protein folding is the process by which a string of amino acids (the chemical building blocks of protein) interacts with itself to form a stable three-dimensional structure during production of the protein within the cell. Folding occurs very rapidly, probably within milliseconds of production of the string of amino acids, and results in 3-D conformations which usually are quite stable, with specific biological functions. The folding of proteins thus facilitates the production of discrete functional entities, including enzymes and structural proteins, which allow the various processes associated with life to occur. Importantly, folding not only allows the production of structures which can perform particular functions in the cellular milieu, but also it prevents inappropriate interactions between proteins, in that folding hides elements of the amino acid sequence which if exposed would react non-specifically with other proteins. Restriction of interactions to those which are necessary and desirable for life is crucial in the intracellular environment where many thousands of proteins are present and required to perform precisely specified functions. Inappropriate folding is one way in which a protein imbalance may arise – the misfolded protein may be nonfunctional or suboptimally functional, or it may be degraded by cellular machinery, or the misfolding may expose epitopes which lead to dysfunctional interactions with other proteins. There are a number of serious diseases which have a common aspect in that they all appear to involve inappropriate folding of a particular protein. These diseases are sometimes lumped together under the heading of the protein misfolding diseases. Many protein misfolding diseases are characterised not by disappearance of a protein but by its deposition in insoluble aggregates within the cell. Diseases caused by protein aggregation include Alzheimer’s disease (deposits of amyloid beta and tau), Type II diabetes (depositis of amylin), Parkinson’s disease (deposits of alpha synuclein), and the spongiform encephalopathies such as Creutzfeldt-Jakob disease (deposits of prion protein). The diagnostic feature common to the protein aggregation diseases is the deposition of insoluble protein aggregates called amyloid fibrils, hence the generic term amyloidosis. The fibrils may themselves be assembled into discrete bodies, termed plaques. In each disease the misfolded protein is unique (ie a different protein is associated with each disease), and a unique set of tissues is affected, but the deposited amyloid fibrils produced by aggregation of the misfolded protein appear structurally very similar. These deposits are found in various subsets of cells, frequently neurons, and may cause their dysfunction and eventual death, with all the typical symptoms of the disease in question. However it should be noted that it is not completely clear whether amyloid fibril deposition is always the cause of disease or merely a symptom of it; and if it is a cause, it is not always clear whether consequent pathology is due to non-functioning of the parent protein or to direct toxicity of the aggregate. Protein misfolding appears at least in some cases to be due to mutations (missing or incorrect amino acids) in the protein which destabilise it such that it is more likely to fold incorrectly. It may be that the more destabilising the mutation, the earlier the onset of disease in the patient, as illustrated by the correlation between onset and the various mutations of the protein transthyretin in familial amyloidotic polyneuropathy. Such destabilising mutations do not always appear inherently to alter the structure or function of the protein, but may simply make it more likely to adopt an inappropriate conformation at some point, and hence to provide the opportunity for inappropriate aggregation. In other cases mutations in the amino acid sequence may directly promote amyloid formation, in that they may increase the likelihood of aggregation of a misfolded protein, rather than increasing the likelihood of it misfolding. However, in many cases amyloid diseases are not clearly associated with genetic mutations; eg Alzheimer’s is quite common in the aged but cases of Alzheimer’s with a clear genetic causation are relatively rare. This may simply be because there are a very wide range of genetic mutations which can give rise to the same disease, of which very few have been identified. Alternatively, the misfolding could occur due to progressively lower levels of chaperone proteins in ageing neurons. Chaperone proteins, such as the heat shock poteins, protect other proteins against misfolding by stabilising them, and usually remove them when misfolded. Lower levels of chaperone proteins, or less effective chaperoning, could be one element of a progressively less well-controlled cellular environment that may be a feature of ageing. It may also be that mutations or other changes in the chaperone proteins themselves cause them to actually promote misfolding, rather than guard against it. As many of the misfolding diseases are manifest in very large numbers of cells, and tend not to be anatomically localized, any such ‘rechaperoning’ therapies would need to diffuse throughout the affected tissues into most cellular compartments, implying a small molecule approach. In addition, as the rechaperones would at best prevent or delay progression of disease, rather than curing the cause of the disease, patients would have to use the therapy for the rest of their lives. If effective, the therapy might also be used prophylactically in symptomless patients to prevent onset of disease.