Conformational Diseases

Despite all cellular protection mechanisms, protein aggregation plays an increasing role in health with age, especially in the light of the increasing life span in Western civilizations. Carrell and Lomas (1997) proposed a new group of disorders, the conformational diseases, which have an important impact on public health, such as AD, PD, Huntington's disease (HD), transmissible spongiform encephalopathies (TSEs) or prion diseases, cystic fibrosis, sickle cell anemia, and other less common conditions such as those summarized in Table 1 (Cairns et al. 2004; Scheibel 2004; Johansson et al. 2004; Aguzzi and Haass 2003; Stojanovic et al. 2003; Ishimaru et al. 2003; Bates 2003; Dawson and Dawson 2003; Stirling et al. 2003; Sandilands et al. 2002; Dobson 2001; Merlini et al. 2001; Avilla 2000; Clark and Muchowski 2000; Damas and Saraiva 2000; Kelly 1998; Carrell and Lomas 1997; Kielty and Shuttleworth 1994; Nishio et al. 1983; see also the chapter by Winklhofer and Tatzelt, this volume). Confor-mational diseases are described as conditions in which a constituent protein undergoes a structural change that results in self-association, aggregation, and tissue deposition (Carrell and Lomas 1997). Conformational diseases can be caused by gene sequence alterations. It is interesting to note that approximately half of the mutations in genetically based conformational disorders change a single amino acid in the polypeptide chain (Krawczak et al. 2000).

In the case of protein aggregation disorders, the formation of oligomers and aggregates exerts a toxic gain-of-function effect on the cell, and cell damage or death is decisive for the clinical phenotype (Dobson 2001). Although the endpoint reflecting the accumulation of aggregated protein is similar for the paradigmatic examples of a-1-antitrypsin deficiency, HD, PD, AD, and prion disease, the pathogenesis in these five diseases is quite different.

In a-1-antitrypsin deficiency, a mutation hinders the proper folding of the protein in the ER of liver cells. The misfolded protein tends to form oligomers that are targeted for degradation (Carrell and Lomas 2002). In heterozygous carriers and in homozygous patients with the lung form of the disease, the capacity of degradation components of the protein quality control system is sufficient to cope with the accumulated protein. However, owing to a yet unexplained decrease in the degradation capacity found in 10%-15% of ho-mozygous patients, the protein aggregates cannot be eliminated in the liver cells of such individuals and they develop cirrhosis-like liver damage and hepatocellular carcinoma (Wu et al. 1994).

The type of pathogenesis as found in HD is shared by at least nine other inherited neurological diseases where the pathogen is a string of glutamine residues, which is part of the respective protein (Sakahira et al. 2002; Taylor et al. 2002; Wanker 2000; Perutz 1999). The mutation that causes HD is an unstable expansion of CAG (encoding glutamine) in the Huntingtin gene. The mutation is inherited in an autosomal dominant manner. In patients with HD, the glutamine repeat length may be more than 55, and the longer the repeat the more prone to aggregation is the fragment. This finding is reflected in earlier disease onset for patients with long repeats compared to patients with shorter strings of glutamine (Zoghbi and Botas 2002).

The glutamine repeat-containing proteins share the tendency to self-aggregation with other cellular proteins, among them a-synuclein and A^-peptide, which are the pathogens considered in a specific subset of PD and AD (Dob-son 2001). Early forms of the diseases are inherited due to mutations in the respective genes, which further promote the self-aggregation of the proteins. Such gain-of-function effects contrast with those found in late-onset forms of PD and AD, where self-aggregating proteins accumulate and participate in the development of degenerative disorders due to an intrinsic conformational instability of the wild-type protein.

Prion diseases or TSEs are rare fatal neurodegenerative diseases of humans and animals (Hetz and Soto 2003; Collinge 2001; Prusiner 1998). Primary symptoms include progressive dementia and ataxia (Ironside and Bell 1997). The hallmark pathologies of TSEs are spongiform degeneration of the brain accompanied by extensive astrogliosis and accumulation of the abnormal, protease-resistant prion protein (PrP) isoform in the central nervous system, which sometimes forms plaques (Budka et al. 1995). TSEs in humans can be divided into three groups: familial, sporadic, and infectious. Human familial TSEs are all associated with different mutations in the PrP gene and include some forms of Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker's (GSS) syndrome, and fatal familial insomnia (FFI) (Prusiner and Scott 1997). Sporadic CJD has not been associated with any known mutation and occurs worldwide with an incidence of 0.5-1.5 new cases per 1 million people each year (Johnson and Gibbs 1998). Infectious TSE diseases include Kuru, which was propagated by ritualistic cannibalism, and iatrogenic CJD, which is spread by tissue transplantation, contamination of surgical tools, or inoculation with materials derived from CJD-infected tissues (Prusiner 1998). New variant CJD (vCJD) is a novel infectious disease, which is strongly linked to exposure to the bovine spongiform encephalopathy (BSE) agent, the most common TSE disease in cattle (Collinge 2001; 1999; Bruce 2000; Wille et al. 1996).

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