Response: Parkinson's disease, pesticides and mitochondrial dysfunction

We appreciate Jenner's thoughtful comments about our recent work on a new model of Parkinson's disease (PD) 1xChronic systemic pesticide exposure reproduces features of Parkinson's disease. Betarbet, R et al. Nat. Neurosci. 2000; 3: 1301–1306Crossref | PubMed | Scopus (2021)See all References1. He raises many of the same issues with which we have been struggling for some time. To put our work into proper perspective, it should be pointed out that we did not set out to establish a link between pesticides and PD. Instead, we were interested in whether a systemic defect in complex I of the mitochondrial respiratory chain could produce the selective nigrostriatal dopaminergic degeneration that characterizes PD. As Jenner points out, several groups have reported a systemic complex I defect in PD; our question was whether it was relevant to PD pathogenesis. To model this systemic mitochondrial abnormality, we used the classical lipophilic complex I inhibitor, rotenone, because it crosses biological membranes easily and independent of transporters. To our surprise, systemic rotenone administration produced highly selective degeneration of precisely the neurones that degenerate in PD, and many dying neurones contained cytoplasmic inclusions similar to the Lewy bodies of PD. Our results clearly suggest that a modest systemic defect in a ubiquitous mitochondrial enzyme might be central to PD pathogenesis.The real question, of course, is how commonly might complex I defects contribute to cases of PD? Jenner suggests that ‘the lack of a detectable change in complex I in many individuals with PD suggests that it cannot underlie nigral degeneration in all individuals with the illness.’ This might or might not be true. Although we certainly would not argue that all ‘idiopathic’ PD is caused by a complex I defect, we believe typical complex I assays are relatively insensitive to all but gross defects. The enzyme assays are usually performed with single, saturating concentrations of NADH and coenzyme Q, and therefore cannot detect altered substrate or co-factor affinities or reduced activity as a result of depressed levels of endogenous substrate or co-factor 2xCoenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Shults, C.W et al. Ann. Neurol. 1997; 42: 261–264Crossref | PubMed | Scopus (189)See all References2. Oxygraphic measurements of respiration using complex I substrates might be even less sensitive as a result of threshold effects 3xThreshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. Davey, G.P and Clark, J.B. J. Neurochem. 1996; 66: 1617–1624Crossref | PubMedSee all References3. As Jenner highlights, we do not know which cell populations in substantia nigra have a complex I defect; however, if in some individuals it is selective for the dopamine neurons (which comprise 1–2% of the local cells), this would certainly not be detectable with conventional assays. Moreover, minimal inhibition of complex I with a concentration of rotenone (5 nm) that reduces enzyme activity very little 4xMitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson's disease. Chinopoulos, C and Adam-Vizi, V. J. Neurochem. 2001; 76: 302–306Crossref | PubMed | Scopus (53)See all References4 (and respiration not at all 1xChronic systemic pesticide exposure reproduces features of Parkinson's disease. Betarbet, R et al. Nat. Neurosci. 2000; 3: 1301–1306Crossref | PubMed | Scopus (2021)See all References1) is sufficient to produce over a period of weeks progressive oxidative damage to protein and DNA and, eventually, apoptotic cell death 5xAn in vitro model of Parkinson's disease: chronic complex I inhibition. Sherer, T.B et al. Soc. Neurosci. Abstr. 2000; 26: 280See all References5. Thus, low-grade complex I defects might be undetectable with conventional assays, yet have catastrophic consequences in the long run. In summary, our results 1xChronic systemic pesticide exposure reproduces features of Parkinson's disease. Betarbet, R et al. Nat. Neurosci. 2000; 3: 1301–1306Crossref | PubMed | Scopus (2021)See all References1 indicate that complex I dysfunction is sufficient to reproduce the features of PD; however, the degree to which complex I defects contribute to typical cases of PD is uncertain, and in our opinion, probably underestimated.Because epidemiological studies have repeatedly implicated pesticides in the pathogenesis of PD, the fact that rotenone is a pesticide was also of interest to us. Our study gives the pesticide hypothesis ‘biological plausibility’. As Jenner notes, several more common pesticides are also potent inhibitors of complex I, and we do not yet know whether these also cause selective nigrostriatal degeneration. However, it is becoming clear that other types of pesticides might also damage the dopamine system 6xThe nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease. Thiruchelvam, M et al. J. Neurosci. 2000; 20: 9207–9214PubMedSee all References6. Nonetheless, we recognize that James Parkinson described the ‘shaking palsy’ long before the widespread use of pesticides. (Interestingly however, rotenone, as crushed derris root, has been used in Europe for hundreds of years.) In this regard, it is essential to recognize that many natural compounds are complex I inhibitors. For example, the piericidins from Streptomyces strains, and the acetogenins from Annonacae plants (such as the custard apple) inhibit complex I more potently than rotenone. The extent to which our food contains – or is contaminated by – such substances is unknown. Even rhubarb contains a weak complex I inhibitor. Thus, there may be reasons other than pesticide exposure to stay out of the garden. Better yet, we should figure out what's in the garden.