Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 14: 501-503
Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, 221 84 Lund, Sweden.Nature medicine (Impact Factor: 27.36). 06/2008; 14(5):501-3. DOI: 10.1038/nm1746
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, Oct 02, 2015
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- "Observations that embryonic dopamine neurons transplanted in PD patients developed a-syn-positive Lewy bodies 11–16 years after surgery (Kordower et al, 2008; Li et al, 2008) have led to the notion that a-syn assemblies released from neurons can propagate in a prion-like manner by seeding the assembly of endogenous a-syn (reviewed in Brettschneider et al, 2015). Several in vitro experiments (exposure to a-syn) and animal models (injection of a-syn) support the seeded aggregation and transmission of a-syn (Desplats et al, 2009; Hansen et al, 2011; Volpicelli-Daley et al, 2011; Luk et al, 2012; Mougenot et al, 2012; Rey et al, 2013; Holmqvist et al, 2014; Sacino et al, 2014; Peelaerts et al, 2015). "
ABSTRACT: Extracellular α-synuclein (α-syn) assemblies can be up-taken by neurons; however, their interaction with the plasma membrane and proteins has not been studied specifically. Here we demonstrate that α-syn assemblies form clusters within the plasma membrane of neurons. Using a proteomic-based approach, we identify the α3-subunit of Na+/K+-ATPase (NKA) as a cell surface partner of α-syn assemblies. The interaction strength depended on the state of α-syn, fibrils being the strongest, oligomers weak, and monomers none. Mutations within the neuron-specific α3-subunit are linked to rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). We show that freely diffusing α3-NKA are trapped within α-syn clusters resulting in α3-NKA redistribution and formation of larger nanoclusters. This creates regions within the plasma membrane with reduced local densities of α3-NKA, thereby decreasing the efficiency of Na+ extrusion following stimulus. Thus, interactions of α3-NKA with extracellular α-syn assemblies reduce its pumping activity as its mutations in RDP/AHC.The EMBO Journal 08/2015; DOI:10.15252/embj.201591397 · 10.43 Impact Factor
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- "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; 207. DOI:10.1016/j.virusres.2015.04.014 · 2.32 Impact Factor
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- "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 · 2.32 Impact Factor