ACCESSION NO:  96-97-1434
       TITLE:  Protein-Folding and Molecular Chaperones: All Tangled Up and 
               Nowhere to Go
      AUTHOR:  EZZELL, CAROL
     JOURNAL:  Journal of NIH Research
    CITATION:  September, 1996: 31-33.
        YEAR:  1996
    PUB TYPE:  Article
 IDENTIFIERS:  PRION DISEASES; SPONGIFORM ENCEPHALOPATHIES; ALZHEIMER'S 
               DISEASE; MOLECULAR CHAPERONES; PROTEIN FOLDING PROCESS; MAD 
               COW DISEASE; CREUTZELD-JAKOB DISEASE; FATAL FAMILIAL 
               INSOMNIA; KURU; CALNEXIN; PROTEIN FOLDING
    ABSTRACT:       Eukaryotic cells filled with misfolded proteins stop 
               performing their normal functions and may interfere with the 
               function of neighboring cells. Molecular chaperones are 
               proteins which help other proteins to fold in the correct way 
               and prevent unfolded or misfolded proteins from sticking 
               together. Molecular chaperones may be defective in a many 
               types of disease from Alzheimer's and cystic fibrosis to 
               prion diseases. In the future, scientists may be able to use 
               small peptides that mimic molecular chaperones to attack 
               protein folding diseases and resort the misfolded proteins 
               which cause the disease.
                    Prions were identified in 1982 and are believed to 
               consist solely of protein, with no nucleic acid to encode 
               their genomes. They are believed to cause the spongiform 
               encephalopathies, including mad cow disease in cattle, 
               scrapie of sheep, and rare human diseases such as fatal 
               familial insomnia, kuru, and the neurodegenerative disorder 
               Creutzfeld-Jakob disease (CJD). Recent research suggests that 
               prions consist of misfolded protein called PrPsc. Prions 
               attack the brain and central nervous system by inducing a 
               normal cellular protein PrPc to misfold. Due to the potential 
               danger of infection and technical difficulty involved in 
               working with prions, some researchers study a prion-like 
               phenomenon in yeast--the cytosolic protein aggregates 
               characteristic of a phenotype called psi (PSI).
                    Researchers report that they are able to "cure" PSI in 
               yeast. PSI is caused by the clumping of a protein, Sup35. 
               Normal Sup35 is involved in stopping mRNA translation into 
               protein. In yeast with PSI, Sup35 is not available. 
               Researchers found that Sup35 clumping required a small amount 
               of mHsp104. Over expression of the gene that encodes Hsp104 
               could prevent Sup35 clumping and deleting the Hsp104 gene had 
               the same effect. The researchers conclude that Hsp104 helps 
               fold Sup35 into shape and that an unstable intermediate form 
               of Sup35 can be co-opted to form clumps characteristic of 
               PSI.
                    Researchers believe that chaperone molecules can help or 
               hurt but in most protein-folding diseases, the chaperones are 
               not functioning properly. The PSI scenario may resemble what 
               occurs in prion-infected mammalian cells. Research suggests 
               that prion PrPc associates with an unidentified protein 
               (protein X) to form the scrapie protein, PrPsc. The molecular 
               chaperone Hsp60 was involved in the only case of a molecular-
               chaperone-related disease so far identified. The patient, a 
               baby in Norway who died at 2 d of age, had only one-fifth the 
               normal amount of Hsp60 in her mitochondria due to a gene 
               mutation. The lack of  Hsp60 contributed to the misfolding of 
               mitochondrial proteins important in energy production. 
               Scientists are working on the connection between calnexin--a 
               molecular chaperone in the endoplasmic reticulum and mutant 
               forms of the cystic fibrosis transmembrane conductance 
               regulator (CFTR) protein in cystic fibrosis, which prevents 
               normal function of chloride channels.
                    Scientists are most interested in using molecular 
               chaperones as drugs, particularly in Alzheimer's disease. The 
               extracellular plaques formed in the brains of Alzheimer's 
               patients are composed of a variant of a normal neuronal 
               protein, amyloid precursor protein, which might be more 
               accessible to drugs than are the misfolded intracellular 
               proteins.