Misfolding diseases

To this list of protein misfolding diseases can be added rare familial amyloidoses in which the mutated proteins have the classic amyloid fibril congophilic birefringence and cross-(3-sheet structure (Table 3). Many of these deposits have an impact on the central nervous system (TTR, cystatin, lysozyme) as well as on other organ systems. A newly described disease, familial British dementia, is associated with the deposition of Abri, a 34 amino acid, 4 kDa peptide cleaved from a 277 amino acid precursor sequence, the last 10 amino acids of which are not normally translated [52]. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is... 

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

Squire,J. (1981). The Structural Basis of Muscle Contraction. Plenum Press, New York. Stefani, M., and Dobson, C. M. (2003). Protein aggregation and aggregate toxicity New insights into protein folding, misfolding diseases and biological evolution. J. Mol. Med. 81, 678-699. 

Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, N., Ramponi, G., Dobson, C. M., and Stefani, M. (2002). Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507-511. 

Kayed, R., Sokolov, Y., Edmonds, B., Mclntire, T. M., Milton, S. C., Hall, J. E., and Glabe, C. G. (2004). Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. /. Biol. Chem. 279, 46363-46366. 

Protein misfolding diseases (Alzheimer s dementia, prion diseases)... 

E. E. Cohen, J. W. Kelly (2003). Therapeutic approaches to protein-misfolding diseases. Nature 426 905-908. 

Orosz, F., Kovacs, G. G., Lehotzky, A., Olah, J., Vincze, O., Ovadi, J. TPPP/p25 from unfolded protein to misfolding disease prediction and experiments. Biol. 

Protein Misfolding Diseases and the Key Role Played by the Interactions of Polypeptides with Water... 

One of the characteristics of proteins that is implied in this explanation of misfolding diseases is that relatively small changes in their sequences as a result of mutation, or of their biological environment in old age, are, at least... 

The Recent Proliferation of Misfolding Diseases and Prospects for Effective Therapies... 

Rochet J-C. Novel therapeutic strategies for the treatment of protein-misfolding diseases. Exp. Rev. Molec. Med. 2007 9 1-33. 

Table 1 List of Protein Misfolding Diseases and the Implicated Proteins and Peptides...

The role of amyloid in type 2 diabetes appears to be complex severe islet dysfunction correlates well with extensive amyloidosis however, the degree of amyloidosis can vary extremely in long term patients. The factors that trigger the onset of the disease are both genetic and environmental. On the other hand, a common qualification of misfolding diseases is that they occur mostly sporadic, without the necessity of mutations. 

Bucciantini M, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002 416 507. 

Dobson CM (2002) Protein misfolding diseases Getting out of shape. Nature 418 729-730... 

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