Article

Propagation of host disease to grafted neurons: Accumulating evidence

Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA.
Experimental Neurology (Impact Factor: 4.7). 09/2009; 220(2):224-5. DOI: 10.1016/j.expneurol.2009.09.016
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    • "This concept of interneuronal spreading is based on Braak's observation that a-synuclein pathology in the brain propagates caudo-rostrally along axonal projections (Braak et al., 2003b). This hypothesis was further supported by the detection of a-synuclein aggregates in transplanted embryonic neurons in Parkinson's disease patients' brains (Li et al., 2008; Kordower and Brundin, 2009b), the observation of neuron-to-neuron transfer of a-synuclein in mouse brain (Desplats et al., 2009), internalization of exogenous a-synuclein fibrils and induction of neuronal a-synuclein aggregation in vitro and in vivo (Emmanouilidou et al., 2010; Nonaka et al., 2010; Volpicelli-Daley et al., 2011; Danzer et al., 2012a; Luk et al., 2012a, b; Mougenot et al., 2012). Recently, exosomes have been implicated in the dissemination of misfolded proteins in a variety of neurodegenerative disorders, including Parkinson's disease (Bellingham et al., 2012; Schneider and Simons, 2013). "
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    ABSTRACT: Extracellular α-synuclein has been proposed as a crucial mechanism for induction of pathological aggregate formation in previously healthy cells. In vitro, extracellular α-synuclein is partially associated with exosomal vesicles. Recently, we have provided evidence that exosomal α-synuclein is present in the central nervous system in vivo. We hypothesized that exosomal α-synuclein species from patients with α-synuclein related neurodegeneration serve as carriers for interneuronal disease transmission. We isolated exosomes from cerebrospinal fluid from patients with Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy as a non-α-synuclein related disorder that clinically overlaps with Parkinson's disease, and neurological controls. Cerebrospinal fluid exosome numbers, α-synuclein protein content of cerebrospinal fluid exosomes and their potential to induce oligomerization of α-synuclein were analysed. The quantification of cerebrospinal fluid exosomal α-synuclein showed distinct differences between patients with Parkinson's disease and dementia with Lewy bodies. In addition, exosomal α-synuclein levels correlated with the severity of cognitive impairment in cross-sectional samples from patients with dementia with Lewy bodies. Importantly, cerebrospinal fluid exosomes derived from Parkinson's disease and dementia with Lewy bodies induce oligomerization of α-synuclein in a reporter cell line in a dose-dependent manner. Our data suggest that cerebrospinal fluid exosomes from patients with Parkinson's disease and dementia with Lewy bodies contain a pathogenic species of α-synuclein, which could initiate oligomerization of soluble α-synuclein in target cells and confer disease pathology.
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    • "The model proved to be a powerful testbed for preclinical drug screening of candidate neuroprotective agents (Stefanova et al., 2008; Schapira, 2008). Further, transplantation of embryonic striatal tissue in the (PLP)-αSYN mouse model has recently identified evidence that αSYN aggregates may compromise graft maturation and integration (Stefanova et al., 2009b; Kordower and Brundin, 2009). Whether the ANS is affected in the transgenic αSYN MSA models has not been addressed so far. "
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    ABSTRACT: Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause manifesting with progressive autonomic failure (AF), cerebellar ataxia and parkinsonism due to neuronal loss in multiple brain areas associated with (oligodendro)glial cytoplasmic alpha-synuclein (alpha SYN) inclusions (GCIs). Using proteolipid protein (PLP)-alpha-synuclein (alpha SYN) transgenic mice we have previously reported parkinsonian motor deficits triggered by MSA-like alpha SYN inclusions. We now extend these observations by demonstrating degeneration of brain areas that are closely linked to progressive AF and other non-motor symptoms in MSA, in (PLP)-alpha SYN transgenic mice as compared to age-matched non-transgenic controls. We show delayed loss of cholinergic neurons in nucleus ambiguus at 12 months of age as well as early neuronal loss in laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and Onuf's nucleus at 2 months of age associated with alpha SYN oligodendroglial overexpression. We also report that neuronal loss triggered by MSA-like alpha SYN inclusions is absent up to 12 months of age in the thoracic intermediolateral cell column suggesting a differential dynamic modulation of alpha SYN toxicity within the murine autonomic nervous system. Although the spatial and temporal evolution of central autonomic pathology in MSA is unknown our findings corroborate the utility of the (PLP)-alpha SYN transgenic mouse model as a testbed for the study of oligodendroglial alpha SYN mediated neurodegeneration replicating both motor and non-motor aspects of MSA.
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    ABSTRACT: Over the last decade, the potential for therapeutic use of stem cell transplantation for cell replacement or as cellular vectors for gene delivery for neurometabolic and neurodegenerative diseases has received a great deal of interest. There has been substantial progress in our understanding of stem cell biology. Potential applications of cell-mediated therapy include direct cell replacement or protection and repair of the host nervous system. Given the complexities of the cellular organization of the nervous system, especially in diseased states, it seems that using stem cells as cellular vectors to prevent or ameliorate neurological disorders rather than cell replacement and the regrowth of damaged circuitry is more likely to succeed in the near term. Recent success in the treatment of lysosomal storage diseases with genetically modified stem cells support this notion. In Alzheimer's and Parkinson's diseases, stem cell therapy is at its early stages and data generated in animal models and clinical trials using other cell types suggest that a combination of gene and stem cell therapy may be an optimal therapeutic paradigm.
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