Article

Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.

Department of Neurology, Columbia University, New York, NY 10027, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2002; 99(22):14524-9. DOI: 10.1073/pnas.172514599
Source: PubMed

ABSTRACT Parkinson's disease (PD) is most commonly a sporadic illness, and is characterized by degeneration of substantia nigra dopamine (DA) neurons and abnormal cytoplasmic aggregates of alpha-synuclein. Rarely, PD may be caused by missense mutations in alpha-synuclein. MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD. Here we show that alpha-synuclein null mice display striking resistance to MPTP-induced degeneration of DA neurons and DA release, and this resistance appears to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance is not due to abnormalities of the DA transporter, which appears to function normally in alpha-synuclein null mice. Our results suggest that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and represent the first demonstration that normal alpha-synuclein function may be important to DA neuron viability.

1 Bookmark
 · 
112 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interactions between genetic factors and environmental exposures are thought to be major contributors to the etiology of Parkinson's disease. While such interactions are poorly defined and incompletely understood, recent epidemiological studies have identified specific interactions of potential importance to human PD. In this review, the most current data on gene-environment interactions in PD from human studies are critically discussed. Animal models have also highlighted the importance of genetic susceptibility to toxicant exposure and data of potential relevance to human PD are discussed. Goals and needs for the future of the field are proposed.
    Neurobiology of Disease 07/2012; · 5.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein aggregation within the central nervous system has been recognized as a defining feature of neurodegenerative diseases since the early 20th century. Since that time, there has been a growing list of neurodegenerative disorders, including Parkinson disease, which are characterized by inclusions of specific pathogenic proteins. This has led to the long-held dogma that these characteristic protein inclusions, which are composed of large insoluble fibrillar protein aggregates and visible by light microscopy, are responsible for cell death in these diseases. However, the correlation between protein inclusion formation and cytotoxicity is inconsistent, suggesting that another form of the pathogenic proteins may be contributing to neurodegeneration. There is emerging evidence implicating soluble oligomers, smaller protein aggregates not detectable by conventional microscopy, as potential culprits in the pathogenesis of neurodegenerative diseases. The protein α-synuclein is well recognized to contribute to the pathogenesis of Parkinson disease and is the major component of Lewy bodies and Lewy neurites. However, α-synuclein also forms oligomeric species, with certain conformations being toxic to cells. The mechanisms by which these α-synuclein oligomers cause cell death are being actively investigated, as they may provide new strategies for diagnosis and treatment of Parkinson disease and related disorders. Here we review the possible role of α-synuclein oligomers in cell death in Parkinson disease and discuss the potential clinical implications. ANN NEUROL 2012.
    Annals of Neurology 08/2012; · 11.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria have long been known as the powerhouse of the cell. However, these organelles are also pivotal players in neuronal cell death. Mitochondrial dysfunction is a prominent feature of chronic brain disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), and cerebral ischemic stroke. Data derived from morphologic, biochemical, and molecular genetic studies indicate that mitochondria constitute a convergence point for neurodegeneration. Conversely, mitochondria have also been implicated in the neuroprotective signaling processes of preconditioning. Despite the precise molecular mechanisms underlying preconditioning-induced brain tolerance are still unclear, mitochondrial reactive oxygen species generation and mitochondrial ATP-sensitive potassium channels activation have been shown to be involved in the preconditioning phenomenon. This review intends to discuss how mitochondrial malfunction contributes to the onset and progression of cerebral ischemic stroke and AD and PD, two major neurodegenerative disorders. The role of mitochondrial mechanisms involved in the preconditioning-mediated neuroprotective events will be also discussed. Mitochondrial targeted preconditioning may represent a promising therapeutic weapon to fight neurodegeneration.
    Frontiers in Aging Neuroscience 01/2010; 2. · 5.20 Impact Factor

Full-text (2 Sources)

View
30 Downloads
Available from
Jun 2, 2014