The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids

Aguzzi, Adriano; Rajendran, Lawrence

doi:10.1016/j.neuron.2009.12.016

Cited by 405 publications

(353 citation statements)

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“…The observed intercellular transfer and seeding abilities of each of these proteins recall some of the features of PrP sc and thus leads to their classification as 'prion-like' proteins or 'prionoids'. [35][36][37][38][39][40][41][42][43] However, it is important to stress that epidemiological studies have not yet presented any evidence of infectivity for any of these proteinopathies, whereas infectious abilities characterize PrP sc . It is not unlikely that the propagation of b-sheet amyloid structures peculiar to each of these proteins shares some common features.…”

Section: Intercellular Transfer Of A-syn In Animal Modelsmentioning

confidence: 99%

“…We, and others, suggested that a mechanism related to the one proposed by Braak might explain the presence of Lewy bodies in the neural grafts too; specifically, pathogen transfer from host cells to grafted cells might occur and induce formation of Lewy bodies in the young neurons. [34][35][36][37][38][39][40][41][42][43] The core of this review will focus on the idea that a-syn is the pathogenic agent that can transfer from one cell to another, thus propagating pathology from diseased neurons to others.…”

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confidence: 99%

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A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded a-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that a-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up a-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. Multiple hypotheses exist to help explain dopamine neuron cell death and Lewy body formation observed in Parkinson's disease (PD). Mutations of the main proteinaceous constituent of Lewy bodies, a-synuclein (a-syn), lead to dominant, familial disease forms. [1][2][3][4][5] More recently, genome-wide association studies (GWASs) identified variants of the a-synuclein gene (SNCA) gene, encoding a-syn protein, that are coupled to increased PD susceptibility, thus clearly linking this protein to idiopathic PD. 6-8 Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent. If a-syn is misfolded because of the action of the unknown agent, it might contribute to the spreading of pathology by moving from one cell to another and triggering misfolding in the recipient cells. If so, it might explain the surprising presence of Lewy bodies in the young neural grafts of transplanted PD patients observed more than a decade after surgery. [18][19][20][21] In this review, we discuss possible mechanisms by which a-syn could spread between cells and have deadly consequences by describing the molecular evidence for a-syn cellular exit, transit to other cells, uptake by cells, intracellular aggregation, and responses to a-syn accumulation.The Relationship Between a-Syn and PD ...

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Section: Intercellular Transfer Of A-syn In Animal Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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“…Propagation of aggregated TDP43 and cell death could be inhibited by treating TDP43 extracts with formic acid, a powerful denaturant, but not by boiling or mild protease treatment, analogous to mammalian prions. Moreover, the newly aggregated TDP43 maintained characteristic biochemical properties reminiscent of prion Bstrains^originally described in mammalian prion diseases [124,125]. fALS-associated mutations in TARDBP are clustered within the prion-like domain of TDP43 [27], and enhance the self-aggregation and seeding behavior of TDP43 fragments [126,127].…”

Section: Alternative Rna-based Mechanismsmentioning

confidence: 86%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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“…Yet, the idea of AD "inducibility" (and furthermore "transmissibility") is being discussed in the broad public. [7][8][9][10] This is not the first time this topic has been debated. 7 Yet the question arises whether human AD can also be induced exogenously, e.g., by accidental or common contact with AD-typical pathological protein aggregates.…”

Section: Introductionmentioning

confidence: 98%

“…Broadly categorized, three levels of induction of pathological changes on protein level can be distinguished: First, conversion of conformations restricted to within a cell's cytosol (e.g., yeast prions); second, conversion of conformations within the secretory system (e.g., extracellular proteins, Aβ) or secretion and uptake of cytosolic proteins (e.g., tau, synuclein, SOD1) including cell-to-cell spreading usually within one organ (CNS); third, true (classic) transmissibility between individuals (e.g., prion diseases). 9,12 The main difference between the second and third is that for the third category, specific (receptor-based) uptake and neuroinvasive mechanisms have to be present. In our opinion, "infectivity" and "transmissibility" should only be used referring to the third category.…”

Section: Introductionmentioning

confidence: 99%