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: 15.05). 12/2009; 64(6):783-90. DOI: 10.1016/j.neuron.2009.12.016
Source: PubMed


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.

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    • "In 2008, it was proposed that misfolded -syn that has been released from neurons into the extracellular space can be taken up by adjacent cells where it seeds further aggregation of endogenous protein [13]. This process was suggested to underpin the spreading of Lewy neuropathology from one brain region to another [14] [15] [16] [17] [18] [19]. Thus, this hypothesis might explain the progressive, stereotypical spreading of intraneuronal -syn aggregates in PD in accordance with the six neuropathological stages proposed by Braak [20] [21]. "
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    ABSTRACT: Currently, several α-synuclein immunotherapies are being tested in experimental Parkinson's disease models and in clinical trials. Recent research has revealed that α-synuclein is not just an intracellular synaptic protein but also exists extracellularly. Moreover, the transfer of misfolded α-synuclein between cells might be a crucial step in the process leading to a progressive increase in deposition of α-synuclein aggregates throughout the Parkinson's disease brain. The revelation that α-synuclein is present outside cells has increased the interest in antibody-based therapies and opens up for the notion that microglia might play a key role in retarding Parkinson's disease progression. The objectives of this review are to describe and contrast the use of active and passive immunotherapy in treating α-synucleinopathies and highlight the likely important role of microglia in clearing misfolded α-synuclein from the extracellular space.
    Journal of Parkinson's Disease 09/2015; 5(3):413-424. DOI:10.3233/JPD-150630 · 1.91 Impact Factor
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    • "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. "
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    Alzheimer's & dementia: the journal of the Alzheimer's Association 04/2015; DOI:10.1016/j.jalz.2015.02.007 · 12.41 Impact Factor
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    • "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]. "
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    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.
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