Search PubMed⌕ Search

Biomedical subjects

F E Cohen

Publications and source records attributed to F E Cohen.

At least 37 records · Page 2Linked to original sources
PubMed2000

Identification of the Cu2+ binding sites in the N-terminal domain of the prion protein by EPR and CD spectroscopy.

Recent evidence indicates that the prion protein (PrP) plays a role in copper metabolism in the central nervous system. The N-terminal region of human PrP contains four sequential copies of the highly conserved octarepeat sequence PHGGGWGQ spanning residues 60-91. This region selectively binds divalent copper ions (Cu(2+)) in vivo. To elucidate the specific mode and site of binding, we have studied a series of Cu(2+)-peptide complexes composed of 1-, 2-, and 4-octarepeats and several sub-octarepeat peptides, by electron paramagnetic resonance (EPR, conventional X-band and low-frequency S-band) and circular dichroism (CD) spectroscopy. At pH 7.45, two EPR active binding modes are observed where the dominant mode appears to involve coordination of three nitrogens and one oxygen to the copper ion, while in the minor mode two nitrogens and two oxygens coordinate. ESEEM spectra demonstrate that the histidine imidazole contributes one of these nitrogens. The truncated sequence HGGGW gives EPR and CD that are indistinguishable from the dominant binding mode observed for the multi-octarepeat sequences and may therefore comprise the fundamental Cu(2+) binding unit. Both EPR and CD titration experiments demonstrate rigorously a 1:1 Cu(2+)/octarepeat binding stoichiometry regardless of the number of octarepeats in a given peptide sequence. Detailed spin integration of the EPR signals demonstrates that all of the bound Cu(2+) is detected thereby ruling out strong exchange coupling that is often found when there is imidazolate bridging between paramagnetic metal centers. A model consistent with these data is proposed in which Cu(2+) is bound to the nitrogen of the histidine imidazole side chain and to two nitrogens from sequential glycine backbone amides.

Amino Acid Sequence↗
PubMed2000

Analysis of protein dimerization and ligand binding of orphan receptor HNF4alpha.

Hepatocyte nuclear factor 4alpha (HNF4alpha) (NR2A1), an orphan member of the nuclear receptor superfamily, binds DNA exclusively as a homodimer even though it is very similar in amino acid sequence to retinoid X receptor alpha (RXRalpha), which heterodimerizes readily with other receptors. Here, experimental analysis of residues involved in protein dimerization and studies on a reported ligand for HNF4alpha are combined with a structural model of the HNF4alpha ligand-binding domain (LBD) (residues 137 to 384). When K300 (in helix 9) and E327 (in helix 10) of HNF4alpha1 were converted to the analogous residues in RXRalpha (E390 and K417, respectively) the resulting construct did not heterodimerize with the wild-type HNF4alpha, although it was still able to form homodimers and bind DNA. Furthermore, the double mutant did not heterodimerize with RXR or RAR but was still able to dimerize in solution with an HNF4alpha construct truncated at amino acid residue 268. This suggests that the charge compatibility between helices 9 and 10 is necessary, but not sufficient, to determine dimerization partners, and that additional residues in the HNF4alpha LBD are also important in dimerization. The structural model of the HNF4alpha LBD and an amino acid sequence alignment of helices 9 and 10 in various HNF4 and other receptor genes indicates that a K(X)(26)E motif can be used to identify HNF4 genes from other organisms and that a (E/D(X)(26-29)K/R) motif can be used to predict heterodimerization of many, but not all, receptors with RXR. In vitro analysis of another HNF4alpha mutant construct indicates that helix 10 also plays a structural role in the conformational integrity of HNF4alpha. The structural model and experimental analysis indicate that fatty acyl CoA thioesters, the proposed HNF4alpha ligands, are not good candidates for a traditional ligand for HNF4alpha. Finally, these results provide insight into the mechanism of action of naturally occurring mutations in the human HNF4alpha gene found in patients with maturity onset diabetes of the young 1 (MODY1).

Acyl Coenzyme A↗
PubMed2000

Doppel is an N-glycosylated, glycosylphosphatidylinositol-anchored protein. Expression in testis and ectopic production in the brains of Prnp(0/0) mice predisposed to Purkinje cell loss.

The Prnd gene encodes a homolog of the cellular prion protein (PrP(C)) called doppel (Dpl). Up-regulation of Prnd mRNA in two distinct lines of PrP gene ablated (Prnp(0/0)) mice, designated Rcm0 and Ngsk, is associated with death of Purkinje cells. Using recombinant Dpl expressed in Escherichia coli and mouse neuroblastoma cells we demonstrate that wild type (wt) Dpl, like PrP(C), adopts a predominantly alpha-helical conformation, forms intramolecular disulfide bonds, has two N-linked oligosaccharides, and is presented on the cell surface via a glycosylphosphatidylinositol anchor. Dpl protein was detected in testis of wt mice. Using Triton X-114 phase partitioning to enrich for glycosylphosphatidylinositol-anchored proteins, Dpl was detected in brain samples from Rcm0 Prnp(0/0) mice but was absent in equivalent samples from wt mice and ZrchI Prnp(0/0) mice, indicating that ectopic expression of this protein may cause cerebellar pathology in Rcm0 mice. Biochemical and structural similarities between PrP(C) and Dpl documented here parallel the observation that ataxic Ngsk Prnp(0/0) mice can be rescued by overexpression of wild-type PrP transgenes, and suggest that cell surface PrP(C) can antagonize the toxic effect of Dpl expressed in the central nervous system.

Amino Acid Sequence↗
PubMed2000

Co-evolution of proteins with their interaction partners.

The divergent evolution of proteins in cellular signaling pathways requires ligands and their receptors to co-evolve, creating new pathways when a new receptor is activated by a new ligand. However, information about the evolution of binding specificity in ligand-receptor systems is difficult to glean from sequences alone. We have used phosphoglycerate kinase (PGK), an enzyme that forms its active site between its two domains, to develop a standard for measuring the co-evolution of interacting proteins. The N-terminal and C-terminal domains of PGK form the active site at their interface and are covalently linked. Therefore, they must have co-evolved to preserve enzyme function. By building two phylogenetic trees from multiple sequence alignments of each of the two domains of PGK, we have calculated a correlation coefficient for the two trees that quantifies the co-evolution of the two domains. The correlation coefficient for the trees of the two domains of PGK is 0. 79, which establishes an upper bound for the co-evolution of a protein domain with its binding partner. The analysis is extended to ligands and their receptors, using the chemokines as a model. We show that the correlation between the chemokine ligand and receptor trees' distances is 0.57. The chemokine family of protein ligands and their G-protein coupled receptors have co-evolved so that each subgroup of chemokine ligands has a matching subgroup of chemokine receptors. The matching subfamilies of ligands and their receptors create a framework within which the ligands of orphan chemokine receptors can be more easily determined. This approach can be applied to a variety of ligand and receptor systems.

Chemokines↗
PubMed2000

Mimicking dominant negative inhibition of prion replication through structure-based drug design.

Recent progress determining the structure of the host-encoded prion protein (PrP(C)) and the role of auxiliary molecules in prion replication permits a more rational approach in the development of therapeutic interventions. Our objective is to identify a new class of lead compounds that mimic the dominant negative PrP(C) mutants, which inhibit an abnormal isoform (PrP(Sc)) formation. A computational search was conducted on the Available Chemicals Directory for molecules that mimic both the spatial orientation and basic polymorphism of PrP residues 168, 172, 215, and 219, which confer dominant negative inhibition. The search revealed 1,000 potential candidates that were visually analyzed with respect to the structure of this four-residue epitope on PrP(C). Sixty-three compounds were tested for inhibition of PrP(Sc) formation in scrapie-infected mouse neuroblastoma cells (ScN2a). Two compounds, Cp-60 (2-amino-6-[(2-aminophenyl)thio]-4-(2-furyl)pyridine-3, 5-dicarbonitrile) and Cp-62 (N'1-(¿5-[(4, 5-dichloro-1H-imidazol-1-yl)methyl]-2-furyl¿carbonyl)-4 methoxybenzene-1-sulfonohydrazide), inhibited PrP(Sc) formation in a dose-dependent manner and demonstrated low levels of toxicity. A substructure search of the Available Chemicals Directory based on Cp-60 identified five related molecules, three of which exhibited activities comparable to Cp-60. Mimicking dominant negative inhibition in the design of drugs that inhibit prion replication may provide a more general approach to developing therapeutics for deleterious protein-protein interactions.

Algorithms↗
PubMed2000

Self-assembly of recombinant prion protein of 106 residues.

The central event in the pathogenesis of prion diseases is a profound conformational change of the prion protein (PrP) from an alpha-helical (PrP(C)) to a beta-sheet-rich isoform (PrP(Sc)). The elucidation of the mechanism of conformational transition has been complicated by the challenge of collecting high-resolution biophysical data on the relatively insoluble aggregation-prone PrP(Sc) isoform. In an attempt to facilitate the structural analysis of PrP(Sc), a redacted chimeric mouse-hamster PrP of 106 amino acids (MHM2 PrP106) with two deletions (Delta23-88 and Delta141-176) was expressed and purified from Escherichia coli. PrP106 retains the ability to support PrP(Sc) formation in transgenic mice, implying that it contains all regions of PrP that are necessary for the conformational transition into the pathogenic isoform [Supattapone, S., et al. (1999) Cell 96, 869-878]. Unstructured at low concentrations, recombinant unglycosylated PrP106 (rPrP106) undergoes a concentration-dependent conformational transition to a beta-sheet-rich form. Following the conformational transition, rPrP106 possesses properties similar to those of PrP(Sc)106, such as high beta-sheet content, defined tertiary structure, resistance to limited digestion by proteinase K, and high thermodynamic stability. In GdnHCl-induced denaturation studies, a single cooperative conformational transition between the unstructured monomer and the assembled beta-oligomer was observed. After proteinase K digestion, the oligomers retain an intact core with unusually high beta-sheet content (>80%). Using mass spectrometry, we discovered that the region of residues 134-215 of rPrP106 is protected from proteinase K digestion and possesses a solvent-independent propensity to adopt a beta-sheet-rich conformation. In contrast to the PrP(Sc)106 purified from the brains of neurologically impaired animals, multimeric beta-rPrP106 remains soluble, providing opportunities for detailed structural studies.

Chromatography, Gel↗
PubMed2000

A synthetic peptide initiates Gerstmann-Sträussler-Scheinker (GSS) disease in transgenic mice.

The molecular basis of the infectious, inherited and sporadic forms of prion diseases is best explained by a conformationally dimorphic protein that can exist in distinct normal and disease-causing isoforms. We identified a 55-residue peptide of a mutant prion protein that can be refolded into at least two distinct conformations. When inoculated intracerebrally into the appropriate transgenic mouse host, 20 of 20 mice receiving the beta-form of this peptide developed signs of central nervous system dysfunction at approximately 360 days, with neurohistologic changes that are pathognomonic of Gerstmann-Sträussler-Scheinker disease. By contrast, eight of eight mice receiving a non-beta-form of the peptide failed to develop any neuropathologic changes more than 600 days after the peptide injections. We conclude that a chemically synthesized peptide refolded into the appropriate conformation can accelerate or possibly initiate prion disease.

Amino Acid Sequence↗
PubMed2000

Scrapie infectivity is independent of amyloid staining properties of the N-terminally truncated prion protein.

The prion protein undergoes a profound conformational change when the cellular isoform (PrP(C)) is converted into the disease-causing form (PrP(Sc)). Limited proteolysis of PrP(Sc) produces PrP 27-30, which readily polymerizes into amyloid. To study the relationship between PrP amyloid and infectivity, we employed organic solvents that perturb protein conformation. Hexafluoro-2-propanol (HFIP), which promotes alpha-helix formation, modified the ultrastructure of PrP amyloid and decreased the beta-sheet content as well as prion infectivity. HFIP reversibly decreased the binding of Congo red dye to the PrP amyloid rods while inactivation of prion infectivity was irreversible. In contrast, 1,1,1-trifluoro-2-propanol (TFIP) did not inactivate prion infectivity but like HFIP, TFIP did alter the morphology of the rods and abolished Congo red binding. Solubilization using various solvents and detergents produced monomeric and dimeric PrP that lacked infectivity. Proteinase K resistance of detergent-treated PrP 27-30 showed no correlation with scrapie infectivity. Our results separate prion infectivity from the amyloid properties of PrP 27-30 and underscore the dependence of prion infectivity on PrP(Sc) conformation. These findings also demonstrate that the specific beta-sheet-rich structures required for prion infectivity can be differentiated from those required for amyloid formation.

Amyloid↗
PubMed2000

Quantitative traits of prion strains are enciphered in the conformation of the prion protein.

Variations in prions, which cause different disease phenotypes, are often referred to as strains. Strains replicate with a high degree of fidelity, which demands a mechanism that can account for this phenomenon. Prion strains differ by qualitative characteristics such as clinical symptoms, brain pathology, topology of accumulated PrP(Sc), and Western blot patterns of glycosylated or deglycosylated PrP(Sc). Since none of these qualitative features can directly explain quantitative strain traits such as incubation time or dose response, we analyzed conformational parameters of PrP(Sc) and the rate of accumulation in different prion strains. Using the conformation-dependent immunoassay (CDI), we were able to discriminate among PrP(Sc) molecules from eight different prion strains propagated in Syrian hamsters. CDI quantifies PrP isoforms by simultaneously following antibody binding to both the denatured and native forms of a protein. In a plot of the ratio of antibody binding to denatured/native PrP graphed as a function of the concentration of PrP(Sc), each strain occupied a unique position, indicating that each strain accumulated different concentrations of particular PrP(Sc) conformers. This conclusion was supported by a unique pattern of equilibrium unfolding of PrP(Sc) found within each strain. By comparing the PrP(Sc) levels before and after limited proteinase K digestion, we found that each strain produces a substantial fraction of protease-sensitive PrP(Sc). We asked whether this fraction of PrP(Sc) might reflect those PrP(Sc) molecules that are most readily cleared by cellular proteases. When the protease-sensitive PrP(Sc) fraction was plotted as a function of the incubation time, a linear relationship was found with an excellent correlation coefficient (r = 0.94). Combined with the data on time courses of prion infection in Tg(MHu2M) and Tg(SHaPrP) mice, the results argue that different incubation times of various prion strains may arise predominantly from distinct rates of PrP(Sc) clearance rather than from different rates of PrP(Sc) formation.

Animals↗
PubMed2000

Aryl ureas represent a new class of anti-trypanosomal agents.

BACKGROUND: The trypanosomal diseases including Chagas' disease, African sleeping sickness and Nagana have a substantial impact on human and animal health worldwide. Classes of effective therapeutics are needed owing to the emergence of drug resistance as well as the toxicity of existing agents. The cysteine proteases of two trypanosomes, Trypanosoma cruzi (cruzain) and Trypanosoma brucei (rhodesain), have been targeted for a structure-based drug design program as mechanistic inhibitors that target these enzymes are effective in cell-based and animal models of trypanosomal infection. RESULTS: We have used computational methods to identify new lead scaffolds for non-covalent inhibitors of cruzain and rhodesain, have demonstrated the efficacy of these compounds in cell-based and animal assays, and have synthesized analogs to explore structure activity relationships. Nine compounds with varied scaffolds identified by DOCK4.0.1 were found to be active at concentrations below 10 microM against cruzain and rhodesain in enzymatic studies. All hits were calculated to have substantial hydrophobic interactions with cruzain. Two of the scaffolds, the urea scaffold and the aroyl thiourea scaffold, exhibited activity against T. cruzi in vivo and both enzymes in vitro. They also have predicted pharmacokinetic properties that meet Lipinski's 'rule of 5'. These scaffolds are synthetically tractable and lend themselves to combinatorial chemistry efforts. One of the compounds, 5'(1-methyl-3-trifluoromethylpyrazol-5-yl)-thiophene 3'-trifluoromethylphenyl urea (D16) showed a 3.1 microM IC(50) against cruzain and a 3 microM IC(50) against rhodesain. Infected cells treated with D16 survived 22 days in culture compared with 6 days for their untreated counterparts. The mechanism of the inhibitors of these two scaffolds is confirmed to be competitive and reversible. CONCLUSIONS: The urea scaffold and the thiourea scaffold are promising leads for the development of new effective chemotherapy for trypanosomal diseases. Libraries of compounds of both scaffolds need to be synthesized and screened against a series of homologous parasitic cysteine proteases to optimize the potency of the initial leads.

Animals↗
PubMed2000

Copper binding to octarepeat peptides of the prion protein monitored by mass spectrometry.

Electrospray ionization mass spectrometry (ESI-MS) was used to measure the binding of Cu2+ ions to synthetic peptides corresponding to sections of the sequence of the mature prion protein (PrP). ESI-MS demonstrates that Cu2+ is unique among divalent metal ions in binding to PrP and defines the location of the major Cu2+ binding site as the octarepeat region in the N-terminal domain, containing multiple copies of the repeat ProHisGlyGlyGlyTrpGlyGln. The stoichiometries of the complexes measured directly by ESI-MS are pH dependent: a peptide containing four octarepeats chelates two Cu2+ ions at pH 6 but four at pH 7.4. At the higher pH, the binding of multiple Cu2+ ions occurs with a high degree of cooperativity for peptides C-terminally extended to incorporate a fifth histidine. Dissociation constants for each Cu2+ ion binding to the octarepeat peptides, reported here for the first time, are mostly in the low micromolar range; for the addition of the third and fourth Cu2+ ions to the extended peptides at pH 7.4, K(D)'s are <100 nM. N-terminal acetylation of the peptides caused some reduction in the stoichiometry of binding at both pH's. Cu2+ also binds to a peptide corresponding to the extreme N-terminus of PrP that precedes the octarepeats, arguing that this region of the sequence may also make a contribution to the Cu2+ complexation. Although the structure of the four-octarepeat peptide is not affected by pH changes in the absence of Cu2+, as judged by circular dichroism, Cu2+ binding induces a modest change at pH 6 and a major structural perturbation at pH 7.4. It is possible that PrP functions as a Cu2+ transporter by binding Cu2+ ions from the extracellular medium under physiologic conditions and then releasing some or all of this metal upon exposure to acidic pH in endosomes or secondary lysosomes.

Amino Acid Sequence↗
PubMed2000

Affinity-tagged miniprion derivatives spontaneously adopt protease-resistant conformations.

An abridged PrP molecule of 106 amino acids designated PrP106 can form infectious miniprions in transgenic (Tg) mice (29). Addition of six-histidine (His(6)) affinity tags to selective sites within PrP106 resulted unexpectedly in new PrP proteins that spontaneously adopted protease-resistant conformations when expressed in neuroblastoma cells and Tg mice. Acquisition of protease resistance depended on the length, charge, and placement of the affinity tag. Introduction of the disease-linked mutation E200K into the sequence of PrP106(140/6His) increased the recovery of protease-resistant PrP fivefold, whereas introduction of the mutations C213A and Delta214-220 did not affect the recovery of protease-resistant PrP. Treatment of cultured cells expressing affinity-tagged PrP106 mutants with polypropyleneimine dendrimer rendered these proteins sensitive to protease digestion in a manner similar to wild-type PrP(Sc). We conclude that certain affinity-tagged PrP106 proteins spontaneously fold into conformations partially resembling, yet distinct from, wild-type PrP(Sc). These proteins might be useful tools in the identification of new disease-causing mutations as well as for screening compounds for therapeutic efficacy.

Animals↗
PubMed2000

Dominant-negative inhibition of prion formation diminished by deletion mutagenesis of the prion protein.

Polymorphic basic residues near the C terminus of the prion protein (PrP) in humans and sheep appear to protect against prion disease. In heterozygotes, inhibition of prion formation appears to be dominant negative and has been simulated in cultured cells persistently infected with scrapie prions. The results of nuclear magnetic resonance and mutagenesis studies indicate that specific substitutions at the C-terminal residues 167, 171, 214, and 218 of PrP(C) act as dominant-negative, inhibitors of PrP(Sc) formation (K. Kaneko et al., Proc. Natl. Acad. Sci. USA 94:10069-10074, 1997). Trafficking of substituted PrP(C) to caveaola-like domains or rafts by the glycolipid anchor was required for the dominant-negative phenotype; interestingly, amino acid replacements at multiple sites were less effective than single-residue substitutions. To elucidate which domains of PrP(C) are responsible for dominant-negative inhibition of PrP(Sc) formation, we analyzed whether N-terminally truncated PrP(Q218K) molecules exhibited dominant-negative effects in the conversion of full-length PrP(C) to PrP(Sc). We found that the C-terminal domain of PrP is not sufficient to impede the conversion of the full-length PrP(C) molecule and that N-terminally truncated molecules (with residues 23 to 88 and 23 to 120 deleted) have reduced dominant-negative activity. Whether the N-terminal region of PrP acts by stabilizing the C-terminal domain of the molecule or by modulating the binding of PrP(C) to an auxiliary molecule that participates in PrP(Sc) formation remains to be established.

Animals↗
PubMed2000

Chalcone, acyl hydrazide, and related amides kill cultured Trypanosoma brucei brucei.

BACKGROUND: Protozoan parasites of the genus Trypanosoma cause disease in a wide range of mammalian hosts. Trypanosoma brucei brucei, transmitted by tsetse fly to cattle, causes a disease (Nagana) of great economic importance in parts of Africa. T. b. brucei also serves as a model for related Trypanosoma species, which cause human sleeping sickness. MATERIALS AND METHODS: Chalcone and acyl hydrazide derivatives are known to retard the growth of Plasmodium falciparum in vitro and inhibit the malarial cysteine proteinase, falcipain. We tested the effects of these compounds on the growth of bloodstream forms of T. b. brucei in cell culture and in a murine trypanosomiasis model, and investigated their ability to inhibit trypanopain-Tb, the major cysteine proteinase of T. b. brucei. RESULTS: Several related chalcones, acyl hydrazides, and amides killed cultured bloodstream forms of T. b. brucei, with the most effective compound reducing parasite numbers by 50% relative to control populations at a concentration of 240 nM. The most effective inhibitors protected mice from an otherwise lethal T. b. brucei infection in an in vivo model of acute parasite infection. Many of the compounds also inhibited trypanopain-Tb, with the most effective inhibitor having a Ki value of 27 nM. Ki values for trypanopain-Tb inhibition were up to 50- to 100-fold lower than for inhibition of mammalian cathepsin L, suggesting the possibility of selective inhibition of the parasite enzyme. CONCLUSIONS: Chalcones, acyl hydrazides, and amides show promise as antitrypanosomal chemotherapeutic agents, with trypanopain-Tb possibly being one of their in vivo targets.

Amides↗
PubMed1999

Elimination of prions by branched polyamines and implications for therapeutics.

We report that branched polyamines, including polyamidoamide dendimers, polypropyleneimine, and polyethyleneimine, are able to purge PrP(Sc), the protease-resistant isoform of the prion protein, from scrapie-infected neuroblastoma (ScN2a) cells in culture. The removal of PrP(Sc) by these compounds depends on both the concentration of branched polymer and the duration of exposure. Chronic exposure of ScN2a cells to low noncytotoxic concentrations of branched polyamines for 1 wk reduced PrP(Sc) to an undetectable level, a condition that persisted at least 3 wk after removal of the compound. Structure-activity analysis revealed that a high surface density of primary amino groups is required for polyamines to eliminate PrP(Sc) effectively from cells. The removal of PrP(Sc) by branched polyamines is attenuated by chloroquine in living cells, and exposure of scrapie-infected brain extracts with branched polyamines at acidic pH rendered the PrP(Sc) susceptible to protease in vitro, suggesting that endosomes or lysozomes may be the site of action. Our studies suggest that branched polyamines might be useful therapeutic agents for treatment of prion diseases and perhaps a variety of other degenerative disorders.

Animals↗
PubMed1999

Antibody binding defines a structure for an epitope that participates in the PrPC-->PrPSc conformational change.

The X-ray crystallographic structures of the anti-Syrian hamster prion protein (SHaPrP) monoclonal Fab 3F4 alone, as well as the complex with its cognate peptide epitope (SHaPrP 104-113), have been determined to atomic resolution. The conformation of the decapeptide is an Omega-loop. There are substantial alterations in the antibody combining region upon epitope binding. The peptide binds in a U-shaped groove on the Fab surface, with the two specificity determinants, Met109 and Met112, penetrating deeply into separate hydrophobic cavities formed by the heavy and light chain complementarity-determining regions. In addition to the numerous contacts between the Fab and the peptide, two intrapeptide hydrogen bonds are observed, perhaps indicating the structure bound to the Fab exists transiently in solution. This provides the first structural information on a portion of the PrP N-terminal region observed to be flexible in the NMR studies of SHPrP 90-231, SHaPrP 29-231 and mouse PrP 23-231. Antibody characterization of the antigenic surfaces of PrPC and PrPSc identifies this flexible region as a component of the conformational rearrangement that is an essential feature of prion disease.

Animals↗
PubMed1999

Protein misfolding and prion diseases.

The prion diseases provide an intriguing connection between protein folding and neurodegenerative disease. In this review, I explore that importance of protein folding and misfolding in the prion diseases. Thermodynamic and kinetic models are examined in an effort to understand infectious, inherited and sporadic forms of these diseases. These concepts can be generalized to gain insight into other disorders of protein aggregation and deposition such as Alzheimer's disease.

Animals↗