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
Source: PubMed
Download full-text


Available from: Patrik Brundin, Oct 13, 2015
16 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Experimental Neurology 08/2010; 224(2):459-64. DOI:10.1016/j.expneurol.2010.05.008 · 4.70 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Neuropharmacology 05/2010; 58(6):845-54. DOI:10.1016/j.neuropharm.2009.12.015 · 5.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately fail to deliver long-term disease modification and lose effectiveness due to the emergence of side effects. Several strategies have been experimentally tested as alternatives for Parkinson's disease, including direct cell replacement and gene transfer through viral vectors. Cellular transplantation of dopamine-secreting cells was hypothesized as a substitute for pharmacotherapy to directly provide dopamine, whereas gene therapy has primarily focused on restoration of dopamine synthesis or neuroprotection and restoration of spared host dopaminergic circuitry through trophic factors as a means to enhance sustained controlled dopamine transmission. This seems now to have been verified in numerous studies in rodents and nonhuman primates, which have shown that grafts of fetal dopamine neurons or gene transfer through viral vector delivery can lead to improvements in biochemical and behavioral indices of dopamine deficiency. However, in clinical studies, the improvements in parkinsonism have been rather modest and variable and have been plagued by graft-induced dyskinesias. New developments in stem-cell transplantation and induced patient-derived cells have opened the doors for the advancement of cell-based therapeutics. In addition, viral-vector-derived therapies have been developed preclinically with excellent safety and efficacy profiles, showing promise in clinical trials thus far. Further progress and optimization of these therapies will be necessary to ensure safety and efficacy before widespread clinical use is deemed appropriate.
    Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine 01/2011; 78(1):126-58. DOI:10.1002/msj.20233 · 1.62 Impact Factor
Show more