Article

The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids

Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
Neuron (Impact Factor: 15.98). 12/2009; 64(6):783-90. DOI: 10.1016/j.neuron.2009.12.016
Source: PubMed

ABSTRACT Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and "infect" neighboring cells. Therefore, many complex diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions--but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.

Download full-text

Full-text

Available from: Adriano Aguzzi, Aug 24, 2015
2 Followers
 · 
135 Views
  • Source
    • "The biochemical and clinical features of SAD resemble those of familial AD (FAD), which is characterized by a clear autosomal dominant inheritance of causative mutations in mainly three genes (APP, PSEN1, and PSEN2) [19] [20]. Growing evidence that protein aggregates of Ab or Tau (encoded by MAPT gene) can spread in the brain and act as local initiators of further aggregation of normal proteins in a " prion-like " fashion [21] [22] [23] [24] [25], provides a mechanistic framework to understand how somatic mutations in the brain could spark neurodegenerative disease. De novo mosaic mutations of AD-relevant genes would create a nidus of mutant cells mixed between normal cells that would continuously produce and release proaggregating proteins. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cause of sporadic Alzheimer's disease (AD) remains unclear. Given the growing evidence that protein aggregates can spread in a "prion-like" fashion, we reasoned that a small population of brain cells producing such "prion-like" particles due to a postzygotic acquired mutation would be sufficient to trigger the disease. Deep DNA sequencing technology should in principle allow the detection of such mosaics. To detect the somatic mutations of genes causing AD present in a small number of cells, we developed a targeted deep sequencing approach to scrutinize the genomic loci of APP, PSEN1, and PSEN2 genes in DNA extracted from the entorhinal cortex, one of the brain regions showing the earliest signs of AD pathology. We also included the analysis of the MAPT gene because mutations may promote tangle formation. We validated candidate mutations with an independent targeted ultradeep amplicon sequencing technique. We demonstrate that our approach can detect single-nucleotide mosaic variants with a 1% allele frequency and copy number mosaic variants present in as few as 10% of cells. We screened 72 AD and 58 control brain samples and identified three mosaic variants with low allelic frequency (∼1%): two novel MAPT variants in sporadic AD patients and a known PSEN2 variant in a Braak II control subject. Moreover, we detected both novel and known pathogenic nonmosaic heterozygous variants in PSEN1 and PSEN2 in this cohort of sporadic AD patients. Our results show that mosaic mutations with low allelic frequencies in AD-relevant genes can be detected in brain-derived DNA, but larger samples need to be investigated before a more definitive conclusion with regard to the pathogenicity of such mosaics can be made. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 04/2015; DOI:10.1016/j.jalz.2015.02.007 · 17.47 Impact Factor
  • Source
    • "It is thought that an intrinsic pathogenic protein misfolds, evades cellular clearance, and then initiates the sequential corruption of other isogeneic protein molecules. Proteins exhibiting properties of self-aggregation and propagation have also been named 'prionoids' [26] [27]. As is referred before, amyloid (A) and tau protein are the typical prionoids in AD and their misfolded forms act as seeds that initiates aggregate formation by recruiting additional unfolded or oligomeric species of the same protein, just like the prions do [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The misfolding and aggregation of specific proteins within nervous system occur in most age-associated neurodegenerative diseases including Alzheimer's disease (AD). This kind of disorders have been classified as the protein misfolding disease or proteopathy which share key biophysical and biochemical characteristics with prion diseases. In AD, β-amyloid (Aβ) and tau protein, capital agents for the senile plaques and intracellular neurofibrillary tangles, are called 'prionoids' indicating that proteins exhibit prion-like properties. In this review, we describe the prion-like mechanisms in the progression that the Aβ and tau are induced to misfold and self-assemble by a process of templated conformational change and then the lesion caused by the pathogenic agents spread out through the cell-to-cell transportation, including release of intracellular seeds by the donor cell, cellular uptake by the recipient and intercellular transport. This hypothesis will suggest new therapeutic strategies for AD, especially valuable in the pre-symptomatic phase.
    Current Alzheimer Research 09/2014; 11(8):755-64. DOI:10.2174/156720501108140910121425 · 3.80 Impact Factor
  • Source
    • "An interesting and important area of future research is the potential role that cell-to-cell transmission of RNA-protein aggregates plays in disease progression. This is an issue, as it now appears that many ''protein-folding'' diseases, such as Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease, can be transmitted between cells in a ''prionoid'' type of mechanism that is poorly understood (Aguzzi and Rajendran, 2009). RNA-protein aggregates forming in these diseases could play a similar role, either by being taken up by neighboring cells after cell death and lysis or by specific mechanisms that transfer material between cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular processes that contribute to degenerative diseases are not well understood. Recent observations suggest that some degenerative diseases are promoted by the accumulation of nuclear or cytoplasmic RNA-protein (RNP) aggregates, which can be related to endogenous RNP granules. RNP aggregates arise commonly in degenerative diseases because RNA-binding proteins commonly self-assemble, in part through prion-like domains, which can form self-propagating amyloids. RNP aggregates may be toxic due to multiple perturbations of posttranscriptional control, thereby disrupting the normal ‘‘ribostasis’’ of the cell. This suggests that understanding and modulating RNP assembly or clearance may be effective approaches to developing therapies for these diseases.
    Cell 08/2013; 154(4). DOI:10.1016/j.cell.2013.07.038 · 33.12 Impact Factor
Show more