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Surprisingly, mice with targeted deletions of<jats:italic>parkin<\/jats:italic>do not recapitulate robust behavioral or pathological signs of parkinsonism. Since Parkin is thought to protect against neurotoxic insults, we hypothesized that the reason Parkin-deficient mice do not develop parkinsonism is because they are not exposed to appropriate environmental triggers. To test this possibility, we challenged Parkin-deficient mice with neurotoxic regimens of either methamphetamine (METH) or 6-hydroxydopamine (6-OHDA). Because Parkin function has been linked to many of the pathways involved in METH and 6-OHDA toxicity, we predicted that Parkin-deficient mice would be more sensitive to the neurotoxic effects of these agents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found no signs consistent with oxidative stress, ubiquitin dysfunction, or degeneration of striatal dopamine neuron terminals in aged Parkin-deficient mice. Moreover, results from behavioral, neurochemical, and immunoblot analyses indicate that Parkin-deficient mice are not more sensitive to dopaminergic neurotoxicity following treatment with METH or 6-OHDA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results suggest that the absence of a robust parkinsonian phenotype in Parkin-deficient mice is not due to the lack of exposure to environmental triggers with mechanisms of action similar to METH or 6-OHDA. Nevertheless, Parkin-deficient mice could be more sensitive to other neurotoxins, such as rotenone or MPTP, which have different mechanisms of action; therefore, identifying conditions that precipitate parkinsonism specifically in Parkin-deficient mice would increase the utility of this model and could provide insight into the mechanism of AR-JP. Alternatively, it remains possible that the absence of parkinsonism in Parkin-deficient mice could reflect fundamental differences between the function of human and mouse Parkin, or the existence of a redundant E3 ubiquitin-protein ligase in mouse that is not found in humans. Therefore, additional studies are necessary to understand why Parkin-deficient mice do not display robust signs of parkinsonism.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2202-6-71","type":"journal-article","created":{"date-parts":[[2005,12,27]],"date-time":"2005-12-27T07:13:27Z","timestamp":1135667607000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity"],"prefix":"10.1186","volume":"6","author":[{"given":"Francisco A","family":"Perez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy R","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard D","family":"Palmiter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2005,12,24]]},"reference":[{"key":"205_CR1","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1212\/WNL.50.5.1346","volume":"50","author":"JM Gorell","year":"1998","unstructured":"Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ: The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. 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