Spongiform encephalopathies: Insights from transgenic models

Aguzzi, Adriano; Brandner, Sebastian; Fischer, Michael B.; Furukawa, Hisako; Glatzel, Markus; Hawkins, Cynthia; Heppner, Frank L.; Montrasio, Fabio; Navarro, Beatriz; Parizek, Petra; Pekařík, Vladimír; Prinz, Marco; Raeber, Alex J.; Röckl, Christiane; Klein, Michael A.

doi:10.1016/s0065-3527(01)56032-7

Cited by 16 publications

(8 citation statements)

References 143 publications

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“…Interestingly, it was shown that only B cells within the secondary lymphoid organs accumulated prions in a PrP C -dependent fashion, while circulating lymphocytes contained no detectable infectivity (415). A series of bone marrow transfer experiments demonstrated that peripheral prion pathogenesis required the physical presence of B cells, but the expression of the cellular prion protein by these cells is dispensable for pathogenesis upon intraperitoneal infection in the mouse scrapie model (11). Adoptive transfer of Prnp ϩ/ϩ bone marrow to Prnp o/o -recipient mice did not suffice to restore infectibility of Prnp-expressing brain grafts, indicating that neuroinvasion was still defective (53), yet intraperitoneal infection occurred efficiently even in B-celldeficient hosts that had been engrafted with B cells from Prnp knockout mice (268,354).…”

Section: A the Lymphoid System In Prion Diseasementioning

confidence: 99%

Prions: Protein Aggregation and Infectious Diseases

Aguzzi¹,

Calella²

2009

Physiological Reviews

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452

449

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Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPC is necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPC may help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.

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Section: A the Lymphoid System In Prion Diseasementioning

confidence: 99%

Prions: Protein Aggregation and Infectious Diseases

Aguzzi¹,

Calella²

2009

Physiological Reviews

Self Cite

452

449

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“…or intravenous administration of agent. Although this shed light on many fundamental aspects of TSE pathogenesis [56–58], it was recognized that such approaches could not properly reflect the transmission of scrapie, BSE, CWD or vCJD as it would occur naturally in the affected hosts. Additionally, it became increasingly evident ‘that the requirements for oral and i.p.…”

Section: Exploration Of the Systemic Spread Of Infection In Naturallymentioning

confidence: 99%

The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies

2007

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Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that are caused by unconventional pathogens and affect the central nervous system of animals and humans. Several different forms of these diseases result from natural infection (i.e. exposure to transmissible spongiform encephalopathy agents or prions, present in the natural environment of the respective host). This holds true also for scrapie in sheep, bovine spongiform encephalopathy in cattle, chronic wasting disease in elk and deer, or variant Creutzfeldt–Jakob disease in humans, all of which are assumed to originate predominantly from peroral prion infection. This article intends to provide an overview of the current state of knowledge on the spread of scrapie, chronic wasting disease, bovine spongiform encephalopathy and variant Creutzfeldt–Jakob disease agents through the body in naturally affected hosts, and in model animals experimentally challenged via the alimentary tract. Special attention is given to the tissue components and spreading pathways involved in the key stages of prion routing through the body, such as intestinal uptake, neuroinvasion of nerves and the central nervous system, and centrifugal spread from the brain and spinal cord to peripheral sites (e.g. sensory ganglia or muscles). The elucidation of the pathways and mechanisms by which prions invade a host and spread through the organism can contribute to efficient infection control strategies and the improvement of transmissible spongiform encephalopathy diagnostics. It may also help to identify prophylactic or therapeutic approaches that would impede naturally acquired transmissible spongiform encephalopathy infections.

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“…This conclusion has been supported by numerous transgenic mouse studies, where mice expressing pathogenetic mutant forms of the human genes encoding each of the aggregating proteins mentioned above show many of the histopathological, neurochemical and behavioural changes associated with the relevant human disease [see, for example, refs. [12][13][14][15][16][17][18][19][20][21][22]. Furthermore, it has been shown that many of the fibril-forming proteins or peptides associated with neurodegenerative diseases are toxic to cultured neuronal cells.…”

Section: The Accumulation Of Extracellular or Intracellular Fibrillarmentioning

confidence: 99%

“…These experiments involving NAC, and some of its fragments, raise the important question as to whether or not toxicity and aggregation are, again, accompanied by hydrogen peroxide generation. NAC , NAC (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), NAC (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), NAC (18-1) and NAC were incubated for periods of up to 48 hrs, following our standard procedure. Of these fragments, the characteristic ESR spectrum of DMPO-OH was observed, upon addition of DMPO, DETAPAC and, finally, Fe(II), for NAC and NAC(1-18) only ( Table 3) [80].…”

Section: Generation Of Hydrogen Peroxide From α-Synucleinmentioning

confidence: 99%

Direct Production of Reactive Oxygen Species from Aggregating Proteins and Peptides Implicated in the Pathogenesis of Neurodegenerative Diseases

Tabner¹,

Turnbull²,

El‐Agnaf³

2003

CMCIEMA

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The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the β-amyloid (Aβ) peptide, which accumulates in the brain in Alzheimer's disease, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown that solutions of Aβ liberate hydroxyl radicals when incubated in vitro, upon the addition of small amounts of Fe(II). We have also obtained similar results with α-synuclein, which accumulates in Lewy bodies in Parkinson's disease, and with the PrP (106-126) toxic fragment of the prion protein. It is becoming clear that some transition metal ions, especially Fe(III) and Cu(II), can bind to these aggregating peptides, and that some of them can reduce the oxidation state of Fe(III) and/or Cu(II). The data suggest that hydrogen peroxide accumulates during incubation of these various proteins and peptides, and is subsequently converted to hydroxyl radicals in the presence of redox-active transition metal ions. Consequently, a fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of ROS during formation of the abnormal protein aggregates.

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Spongiform encephalopathies: Insights from transgenic models

Cited by 16 publications

References 143 publications

Prions: Protein Aggregation and Infectious Diseases

Prions: Protein Aggregation and Infectious Diseases

The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies

Direct Production of Reactive Oxygen Species from Aggregating Proteins and Peptides Implicated in the Pathogenesis of Neurodegenerative Diseases

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