Protein encephalopathy

The transmissible spongiform encephalopathies, or prion diseases, are fatal neurodegenerative diseases characterized by spongiform changes, astrocytic gliomas, and neuronal loss resulting from the deposition of insoluble protein aggregates in neural cells. They include Creutzfeldt-Jakob disease in humans, scrapie in... 

Prions—protein particles that lack nucleic acid— cause fatal transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease, scrapie, and bovine spongiform encephalopathy. Prion diseases involve an altered secondary-tertiary strucmre of a namrally occurring protein, PrPc. When PrPc interacts with its pathologic isoform PrPSc, its conformation is transformed from a predominantly a-helical strucmre to the P-sheet strucmre characteristic of PrPSc. 

Add protein back in 20 g increments every 3-5 d once acute hepatic encephalopathy improves and until protein caloric goal is achieved (usually 0.8-1 g/kg/d)... 

Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic by-product of protein catabolism and is also generated by bacteria in the GI tract. In a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is then renally excreted. In patients with cirrhosis, the conversion of ammonia to urea is retarded and ammonia accumulates, resulting in encephalopathy. This decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN), but BUN levels do not correlate with degree of HE. Patients with HE commonly have elevated serum ammonia concentrations, but the levels do not correlate well with the degree of central nervous system impairment.20... 

Patients with previously stable cirrhosis who develop acute encephalopathy often have an identifiable precipitating event that can account for the increased production and/or decreased elimination of these toxins. Infections, variceal hemorrhage, renal insufficiency, electrolyte abnormalities, and increased dietary protein have all been associated with acute development of HE. 

In acute hepatic encephalopathy, temporary protein restriction to decrease the rate of ammonia production can... 

Western blot A method to detect protein in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate denatured proteins by mass. Some diagnostic applications for the Western blot include Lyme disease, bovine spongiform encephalopathy, and human immunodeficiency virus (HIV) (it is considered the gold standard for HIV diagnostic testing). 

Prion diseases resulting in encephalopathy can be transmitted between individuals within species (more rarely between species) [26-28], A conformational variant of the normal cellular protein PrPs (PrPc) (protease-sensitive or cellular) is believed to catalyze [29] or nucleate [30-33] conversion to the pathological form, PrPR (protease-resistant). This highly unusual nongenetic mode of transmission of an infectious agent has been strongly debated [29]. The observation of multiple examples of nucleated catalysis of aberrant polymerization of protein subunits has... 

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. 

Modified amino acid solutions are designed for patients with altered protein requirements associated with hepatic encephalopathy, renal failure, and metabolic stress or trauma. However, these solutions are expensive and their role in disease-specific PN regimens is controversial. 

The normal cellular form of prion protein (PrPc) can exist as a Cu-metalloprotein in vivo (492). This PrPc is a precursor of the pathogenic protease-resistant form PrPsc, which is thought to cause scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt—Jakob disease. Two octa-repeats of PHGGGWGQ have been proposed as Cu(II) binding sites centered on histidine (493). They lack secondary and tertiary structure in the absence of Cu(II). Neurons may therefore have special mechanisms to regulate the distribution of copper. 

Pathological conditions are also linked to posttranslational modifications such as oxidized histidine residues found in P-amyloid protein of Alzheimer s patients, or conformational variants in the case of prion-induced encephalopathies. The development of sensitive MS tools and proteomics techniques is playing an active role in the precise description of these mechanisms.97,98... 

In certain cases, serum (fetal bovine serum—FBS) is added to promote the growth of cells. However, the bovine spongiform encephalopathy (BSE) problem has necessitated tight control on the quality of FBS (refer to Exhibit 10.12). This increases production and downstream processing costs. For new cell lines being developed, serum-free and protein-free media are used to circumvent the possibility of virus contamination from animal sources and the variation that may arise from use of serum from animal herds. 

Bovine spongiform encephalopathy (BSE or mad cow disease) is a progressive neurological degenerative disease in cattle. It is caused by a mutated protein called a prion. BSE was first reported in the United Kingdom in 1986. Creutzfeldt-Jakob disease (CJD) is a rare disease that occurs in humans. Evidence to date indicates it is possible for humans to acquire CJD after consuming BSE-contaminated cattle products. 

With the background of the mad cow crisis in Europe, questions relating to the prion diseases have attracted intensive interest. It is now widely accepted that prion diseases, such as Creutzfeldt-Jakob disease (CJd) in humans and bovine spongiform encephalopathy (BSE) are caused by a conformational change of the prion protein (PrP) from a normally folded cellular form, PrP ", to an alternate, aggregation-prone, pathogenic scrapie form,... 

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