Resistance of -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.

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Available from: Anne-Cécile Trillat, Aug 24, 2015
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    • "Snca −/− mice exhibited a marked decrease in the pool of undocked synaptic vesicles in the hippocampus and significant impairments in synaptic response to a prolonged repetitive stimulation, but these mice had no evidence of severe sensory or motor abnormalities, and no attenuation in amphetamine-induced locomotor activity different from the previous study (Abeliovich et al., 2000), which suggested that the ␣-synuclein proteins may be required for the genesis and/or maintenance of a subset of presynaptic vesicles, and may be involved in regulating synaptic vesicle mobilization at nerve terminals (Cabin et al., 2002). Snca −/− mice displayed striking resistance to MPTP-induced degeneration of DA neurons and DA release, demonstrating that normal ␣-synuclein function may be important to DA neuron viability and ␣-synuclein abnormality may modify the vulnerability of DA neurons to an environmental toxin (Dauer et al., 2002). Similarly, Schlüter et al. (2003) also reported that Snca knockout mice showed a partial protection against MPTP toxicity and were slightly more sensitive to methamphetamine, different from mice carrying the spontaneous deletion of the Snca gene, and demonstrated that the ␣-synuclein proteins may have no major role in MPTP toxicity which is different from studies by Richfield et al. (2002), but can influence MPTP toxicity on some genetic backgrounds. "
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    • "In animal studies, overexpression of human α-synuclein leads to degeneration of nerve terminals and locomotor defects (Tofaris et al., 2006; Chung et al., 2009a, 2009b) and such changes can be reversed when the transgene is switched off (Lim et al., 2011). Conversely, knockout of α-synuclein in mice confers protection against certain toxins (Dauer et al., 2002). Therefore, promoting the degradation of α-synuclein and thus reducing its basal level inside neurons could represent a novel neuroprotective strategy for PD. "
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    Neurobiology of Disease 12/2013; 64(100). DOI:10.1016/j.nbd.2013.12.011 · 5.20 Impact Factor
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    • "The A30P αsynuclein mutation has been shown to prevent α-synuclein binding vesicular membranes and to promote oligomerization rather than fibrillization (Conway et al., 2000; Jensen et al., 1998). When we challenged the hα-syn and A30P mice with an acute dose of MPTP both the wild-type and A30P α-synuclein transgenes restored susceptibility to the otherwise resistant Snca−/− line, supporting the concept that the lipid binding ability of α-synuclein does not mediate MPTP toxicity and that A30P α-synuclein is active and able to fully complement the Snca−/− KO background (Dauer et al., 2002; Nemani et al., 2010). Previously , wildtype human α-synuclein and A53T mutated human αsynuclein have been shown to restore MPTP susceptibility in Snca−/− KO mice (Thomas et al., 2011). "
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