Conformational diseases

Y Levy, OM Becker. Wild-type and mutant prion proteins Insights from energy landscape analysis. In E Katzir, B Solomon, A Taraboulos, eds. Conformational Diseases. In press. 

Carrell RW, Lomas DA Alphai-antitrypsin deficiency—a model for conformational diseases. N Engl J Med 2002 346 45. 

New information has been added in appropriate chapters on hpid rafts and caveolae, aquaporins, connexins, disorders due to mutations in genes encoding proteins involved in intracellular membrane transport, absorption of iron, and conformational diseases and pharmacogenomics. 

The failure of proteins to fold into their functional forms can occasionally lead to "misfolding" or "conformational" diseases.140 Many of these diseases are associated with the formation of amyloid protein, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. They include amyloid Ap protein as the major constituent of the plaques in Alzheimer patients, PrPc associated with neuro-degenerative diseases, a-synuclein (AS) associated with Parkinson s diseases, transthyretin (TTR) as a homotetrameric protein that is involved in the transport of thyroid hormones and retinol in human serum. In particular, the Ap protein is a peptide of 39-43 amino acids that is the... 

Zerovnik, E. 2002. Amyloid-fibril formation. Proposed mechanisms and relevance to conformational disease. Eur J Biochem. 269 3362-71. 

Solomon, B. 2002. Anti-aggregating antibodies, a new approach towards treatment of conformational diseases. Current medicinal chemistry 9 1737-1749. 

Table 8.1 Major characteristics of selected conformational diseases (selected data from [54]).

Table 8.2 Involvement of glycolytic enzymes in impairing the energy metabolism of conformational diseases.

The impairment of glucose utilization could result from the modification of the glycolytic enzymes under oxidative stress effects. Oxidative stress is an important factor leading to the pathophysiologcal alterations in conformational diseases. Oxidative stress is manifested in protein oxidation, lipid peroxidation, DNA oxidation, and advanced glycation end-products, as well as reactive oxygen species (ROS), and reactive nitrogen species (RNS) formation. Either the oxidants or the products of oxidative stress could modify the proteins or activate other pathways that may lead to additional impairment of cellular functions and to neuronal loss [57, 58]. 

Momoi, T. (2006) Conformational diseases and ER stress-mediated cell death apoptotic cell death and autophagic cell death. Curr. Mol. Med. 6, 111-118. 

Uversky VN, Fink AL. Protein Misfolding, Aggregation and Conformational Diseases Part A Protein Aggregation and Conformational Diseases Series Protein Reviews. Volume 4. 2006. Springer, New York. 

The amyloidoses are a class of conformational diseases that arise from the conversion of normally unfolded or globular proteins into fibrillar aggregates that are either pathogenic or non-functional. At present there are more than 20 proteins that are associated with human amyloid diseases. This review focuses on three natively unfolded proteins that form fibrillar aggregates amyloid-, islet amyloid polypeptide ( amylin ), and a-synuclein, the diseases they contribute to and chemical and biophysical approaches that are used to investigate these proteins aggregation. 

Bernier V, Lagace M, Bichet DG, Bouvier M. Pharmacological chaperones potential treatment for conformational diseases. Trends Endocrinol. Metab. 2004 15 222-228. 

Carrell, R.W., Lomas, D.A. Mechanisms of disease-Alpha-1-antitrypsin deficiency. A model for conformational diseases (review). New Engl. J. Med. 2002 346 45-53... 

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