Article

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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    • "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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