At a time when there is mounting biochemical evidence for the essential nature of correct trace-element balance to neuronal activity and resistance to neurodegenerative disease there is a paucity of research on how trace element dietary status effects livestock animals.
With threats like TSEs fully in public view it is astounding that the care of animals and how their diet might expose them to such neurodegenerative and possibly transmissible diseases is largely ignored. While genetic status of an animal is an important consideration in this molecular age, it remains a fact that the phenotype of an animal is what is important and diet remain the single most critical regulator, aside from genetic information, that determines what that phenotype will be.
* Mineral imbalance and ruminant health
At a time when there is mounting biochemical evidence for the essential nature of correct trace-element balance to neuronal activity and resistance to neurodegenerative disease there is a paucity of research on how trace element dietary status effects livestock animals. With threats like TSEs fully in public view it is astounding that the care of animals and how their diet might expose them to such neurodegenerative and possibly transmissible diseases is largely ignored. While genetic status of an animal is an important consideration in this molecular age, it remains a fact that the phenotype of an animal is what is important and diet remain the single most critical regulator, aside from genetic information, that determines what that phenotype will be. On this background, Betty Stikkers' experiments on the role of trace-elements in sheep health are likely to provide interesting and important information. As these experiments are supported by a panel of international and experienced research scientists and it is important that these experiments continue.
Dr. David R. Brown*
* Consequences of Manganese replacement of Copper for prion protein function and proteinase resitance:
The pron protein (PrP) binds copper and has antioxidant activity enhancing the survival of neurones in culture:
Brown et al
* A case for the role of copper deficiency in "mad-Cow"disease and human Creutzfeld-Jakob disease:
It has been recognized for centuries that copper plays a vital role in medicine. Since 1928 we have also known that copper is an essential element in human, animal and plant nutrition. It has recently been suggested that copper also affects a newly indentified class of ailmanets known as prion diseases.
Dresher et al
* Copper chelation delays the onset of prion disease:
The prion protein (PrP) binds copper and under some conditions copper can facilitate its folding into a more protease resistant form. Hence, copper levels may influence the infectivity of the scrapie form of prion protein (PrPsc).
Sigurdsson et al
* Discuss a re-evaluation of the TSE enigma and explore the role of environmental factors in prion diseases:
Despite extensive research and an equally wide-ranging BSE Public Inquiry chaired by Lord Phillips, there is much that is unanswered or mainly speculative and it is time for a re-evaluation of the collated information, together with more recent investigations shich have an important bearing on the pathogenesis on the unique class of diseases.
Brown & Haywood
* BSE did not cause variant CJD: an alternative cause related to post-industrial environmental contamination:
The new prion diseases that have emerged in the last 15 years are BSE and variant CJD. Although initially confined to the UK, thesse diseases have emerged in other European countries. The accepted cause of the human disease is that BSE spread from cattle to humans by the consumption of infected beef. However, the evidence that supports this is very thin. Brown
* Aberrant metal binding by prion protein in human prion disease:
Human prion diseases are characterized by the conversion of the normal protein (PrPc) into a pathogenic isomer (PrPSc). Distinct PrPSc conformers are associated with different subtypes of prion diseases. PrPC binds copper and has antioxidation activity. Changes in metal-ion occupancy can lead to significant decline of the antioxidation activity and changes in conformation of the protein.
Wong et al
* Prions show their metal:
Ian Jones describes the evidence that increasingly links prion proteins and copper ions. Could a defect in the metabolism of this simple metal be at the heart of 'mad cow' disease? Jones
Metal imbalance and compromised antioxidant function are early changes in prion disease:
The prion protein (PrP) has been shown to bind copper. In the present study we have investigated whether prion disease in a mouse scrapie model resulted in modifications of metal concentrations. We found changes in the levels of copper and manganese in the brains of scrapie-infected mice prior to the onset of clinical symptoms. Interestingly, we noted a major increase in blood manganese in the early stages of disease.
Thackray et al
* The structure function relationship for the Prion protein:
Central to Prion diseases is the normal endogenous Prion protein, PrPC. In spite of years of research the exact function of this protein remains enigmatic. Numerous binding partners have been identified for PrPC and due to the presence of a repeated sequence of PHGGGWGQ in the proteins amino-terminus it can bind metal ions.
Deignan et al
* Trace element (nutritional) theory of 'mad cow' disease:
Even if the prion-only theory of BSE proves to be substantially correct, copper and other trace metals may have a key role in controlling infectivity of this molecule. It now appears that the normal prion protein (PrP) of nerve cells in the brain could have a key role in the critical functions of copper in the brain.
* Molybdenum toxicity in cattle: an underestimated problem:
Molybdenum toxicity is a controversial subject. However, much of the contention is due to inappropriate diagnosis. This paper shows the flaw in using plasma copper levels alone to diagnose a bolybdenum toxic condition, based on samples from >7.500 dairy cattle.
Telfer et al
* A Delicate Balance: Homeostatic Control of Copper Uptake and Distribution:
The cellular uptake and intracellular distribution of the essential but highly toxic nutrient, copper, is a precisely orchestrated process. Copper homeostasis is coordinated by several proteins to ensure that it is delivered to specific subcellular compartments and copper-requiring proteins without releasing free copper ions that will cause damage to cellular components. Genetic studies in prokaryotic organisms and yeast have identified membrane-associated proteins that mediate the uptake or export of copper from cells.
* Copper Converts the Cellular Prion Protein into a Proteaseresistant Species That Is Distinct from the Scrapie Isoform:
Several lines of evidence have suggested that copper ions play a role in the biology of both PrPC and PrPSc, the normal and pathologic forms of the prion protein.
Elena Quaglio et al
* Copper Stimulates Endocytosis of the Prion Protein:
Prion diseases result from conformational alteration of PrPC, a cell surface glycoprotein expressed in brain, spinal cord, and several peripheral tissues, into PrPSc, a protease-resistant isoform that is the principal component of infectious prion particles.
* Electron Paramagnetic Resonance Evidence for Binding of Cu21 to the C-terminal Domain of the Murine Prion Protein:
Transmissible spongiform encephalopathies in mammals are believed to be caused by scrapie form of prion protein (PrPSc), an abnormal, oligomeric isoform of the monomeric cellular prion protein (PrPC). One of the roposed functions of PrPC in vivo is a Cu(II) binding activity. Grazia M. Cereghetti et al
* Ionic Strength and Transition Metals Control PrPSc Protease Resistance and Conversion-inducing Activity:
The essential component of infectious prions is a misfolded protein termed PrPSc, which is produced by conformational change of a normal host protein, PrPC. It is currently unknown whether PrPSc molecules exist in a unique conformation or whether they are able to undergo additional onformational changes.
Koren Nishina et al
* Mayhem of the multiple mechanisms: modelling neurodegeneration in prion disease:
This review examines recent attempts to advance the understanding of the mechanism by which neurones die in prion disease.
* Metal Toxicity and Therapeutic Intervention:
Copper and prion diseases
* Myocardial cytochrome c oxidase activity in Swedish moose (Alces alces L.) affected by molybdenosis.
Since the mid-19809s, a ‘mysterious’ wasting disease has been afflicting the moose population of south-western Sweden. In 1994 molybdenosis combined with copper deficiency was suggested as the cause of this complex syndrom of clinical signs, diversity of necropsy findings and changes in trace element concentrations.