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Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT. An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci. 2002 Aug 15;22(16):7006-15. PubMed.
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Interesting study to link rotenone's inhibition of complex I with PD pathology, i.e. alpha-synuclein and ubiquitin abnormalities and cell death.
Boston University School of Medicine
Developing adequate cell culture models of synuclein aggregation has proved challenging, and this paper makes a significant step forward. It is curious that the process is so slow, given that the cells divide and likely don't exist in the same state (as one non-dividing cell) for 4 weeks. However, the slow kinetics of rotenone toxicity is consistent with prior studies with compound.
University of Pittsburgh
The work by Tim Greenamyre, Todd Sherer, and colleagues provides a novel cellular model of chronic environmental toxin exposure that may well be relevant to Parkinson’s disease (PD). Although the authors did not use dopaminergic neurons (which they discuss in their paper) the data are nonetheless intriguing. Chronic low-dose rotenone treatment of a dividing neuronal cell line, SKN-MC, induced accumulation of endogenous α-synuclein protein in parallel with ubiquitin accumulation. Both soluble and insoluble α-synuclein protein levels increased, while α-synuclein mRNA did not. The data infer that rotenone contributes to α-synuclein protein stability. These findings are similar to studies by Dino Di Monte and colleagues (Manning-Bog et. al, 2002 ) in which non-transgenic mice expressing endogeonous levels of α-synuclein developed α-synuclein aggregates in substantia nigra neurons after treatment with the herbicide paraquat.
The relevance of both studies, in cells and animals expressing endogenous wild-type α-synuclein, is that they begin to model what may occur in the more prevalent non-familial forms of PD. SKN-MC cells also exhibited reduced glutathione levels and had increased DNA and protein damage after chronic low-dose rotenone. Remarkably, the cells exhibited almost no apoptosis even after 4 weeks of rotenone treatment unless they were further stressed by H2O2 treatment. However, that endogenous levels of wild-type α-synuclein can be stimulated to aggregate secondary to environmental toxins in a manner to make neuronal cells more vulnerable is an important observation. In addition, these models are in line with anecdotal reports from patients with idiopathic PD, who attribute the onset of their parkinsonian symptoms to the use of herbicides. It will now be important to elucidate the mechanism(s) contributing to altered α-synuclein stability, and to determine how such changes impact neuronal viability.
References:
Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem. 2002 Jan 18;277(3):1641-4. PubMed.
View all comments by Ruth PerezVery interesting study to link environmental toxins like rotenone with the development of PD. The development of cellular model of alpha-synuclein aggregation is important to understand the molecular mechanism of alpha-synuclein toxicity and screening for inhibitors of alpha-synuclein aggregation and toxicity.
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