Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature Med. 14, 501-503
ABSTRACT Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.
Full-textDOI: · Available from: Peter Hagell, Aug 28, 2015
- SourceAvailable from: Joaquín Castilla
[Show abstract] [Hide abstract]
- "Although some downstream toxicity mechanisms have been tested in AD (Schilling et al., 2008; Lopes et al., 2010), it is still far from its complete understanding. The idea of close relationship between different protein misfolding related diseases is stronger every day as proven by some recent works showing PrP mediated A␤ toxicity (Larson et al., 2012; Younan et al., 2013; Wang et al., 2013) and could help to understand the cross-seeding phenomenon as the one shown by Morales and collaborators where prion inoculation in an AD model accelerated both pathologies (Morales et al., 2010, 2013). "
ABSTRACT: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a β-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease-specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease. Copyright © 2015. Published by Elsevier B.V.Virus Research 04/2015; DOI:10.1016/j.virusres.2015.04.014 · 2.83 Impact Factor
[Show abstract] [Hide abstract]
- "Indeed, the first indication about prion-like transmission of the alpha-synuclein protein came from three studies published simultaneously in 2008 (Kordower et al., 2008; Li et al., 2008; Mendez et al., 2008). These articles discussed the examination of postmortem brains of PD patients who participated in clinical trials involving grafts of fetal nigral dopaminergic nerve cells into the brains. "
ABSTRACT: Parkinson's disease is one of several neurodegenerative diseases associated with a misfolded, aggregated and pathological protein. In Parkinson's disease this protein is alpha-synuclein and its neuronal deposits in the form of Lewy bodies are considered a hallmark of the disease. In this review we describe the clinical and experimental data that have led to think of alpha-synuclein as a prion-like protein and we summarize data from in vitro, cellular and animal models supporting this view.Virus Research 11/2014; 42. DOI:10.1016/j.virusres.2014.10.016 · 2.83 Impact Factor
[Show abstract] [Hide abstract]
- "The mechanism by which the pathology can propagate through the nervous system is not known. However, evidence for a prion-like mechanism of the ␣-synuclein spreading was provided by the observation that healthy neurons grafted in the brain of a patient with PD gradually developed aggregates of ␣-synuclein similar to those of the host neurons (Kordower et al., 2008; Li et al., 2008). Desplats and collaborators have shown that ␣-synuclein released from neuronal cells over-expressing the protein was transmitted via endocytosis to neighboring neurons, forming LBs-like inclusions. "
ABSTRACT: Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. Copyright © 2014. Published by Elsevier B.V.Virus Research 10/2014; DOI:10.1016/j.virusres.2014.10.020 · 2.83 Impact Factor