Tuesday, May 29, 2012

Transmissible Proteins: Expanding the Prion Heresy

Transmissible Proteins: Expanding the Prion Heresy

Claudio Soto1,*

1Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, Houston, TX 77030, USA

*Correspondence: claudio.soto@uth.tmc.edu

DOI 10.1016/j.cell.2012.05.007

The once heretical concept that a misfolded protein is the infectious agent responsible for prion diseases is now widely accepted. Recent exciting research has led not only to the end of the skepticism that proteins can transmit disease, but also to expanding the concept that transmissible proteins might be at the root of some of the most prevalent human illnesses. At the same time, the idea that biological information can be transmitted by propagation of protein (mis)folding raises the possibility that heritable protein agents may be operating as epigenetic factors in normal biological functions and participating in evolutionary adaptation.


The Prion Principle in Other Protein Misfolding Disorders

The transformation of a natively folded protein into a misfolded, toxic form that causes tissue damage and disease is not a mechanism that is exclusive to prion diseases. Misfolded protein aggregates are implicated in more than 20 human diseases, collectively called protein misfolding disorders (PMDs), including highly prevalent and insidious illnesses such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes (Soto, 2003; Chiti and Dobson, 2006). Although the proteins implicated in each of these pathologies and the clinical manifestations of the diseases differ, the molecular mechanism of protein misfolding is strikingly similar. Unfortunately, despite the extensive knowledge about the molecular basis of these disorders, the factors that trigger protein misfolding and initiate the pathology remain unknown.


A series of recent studies has provided experimental evidence for prion-like mechanisms of pathological transmission in various common neurodegenerative diseases (Table 1). Alzheimer’s disease (AD) is associated with the misfolding and aggregation of two proteins: amyloid-b (Ab) accumulation in extracellular amyloid plaques and hyperphosphorylated tau, which forms neurofibrillary tangles inside of neurons. To assess the possibility that AD pathology might be transmissible by a prion-like mechanism, transgenic mice expressing the human amyloid protein were injected intracerebrally with diluted brain homogenates derived from AD patients (Kane et al., 2000; Meyer-Luehmann et al., 2006). The results clearly showed accelerated Ab-deposition in the brain of inoculated animals.


The recent developments in the field have demonstrated that misfolded proteins associated with various PMDs can initiate the conversion of the normal form of the protein into the misfolded form and propagate these changes to neighboring cells in experimental models. The exciting goal for future research is to determine whether misfolded proteins implicated in PMDs are infectious and transmit disease under natural conditions. In other words, we need to carefully assess whether misfolded proteins are transmitted between individuals and propagate within communities as conventional infectious agents. Despite the excitement generated by the recent findings, the strongest evidence for transmissibility in PMDs other than TSEs was generated by earlier studies in secondary reactive amyloidosis, which is associated with amyloid-A protein aggregation (Lundmark et al., 2002), and mouse senile amyloidosis, which is related to apolipoprotein AII aggregation (Xing et al., 2001) (Table 1). In these diseases, even tiny quantities of misfolded aggregates can be transmitted between individuals and can cause disease by diverse routes, including blood transfusion and oral administration. In the case of amyloid-A amyloidosis, evidence also exists for natural transmission in captive cheetah populations (Zhang et al., 2008).

Thursday, May 24, 2012

Wednesday, May 16, 2012

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Proposal ID: 29403


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