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Parkinson's disease, pesticides and mitochondrial dysfunction
Research Update
TRENDS in Neurosciences Vol.24 No.5 May 2001
245
Research News
Parkinson’s disease, pesticides and mitochondrial dysfunction Peter Jenner Selective nigral degeneration with inclusion formation provoked by systemic administration of the herbicide rotenone, through inhibition of complex I, raises the question of pesticide exposure and environmental factors in general, as a cause of Parkinson’s disease (PD). Toxininduced complex I inhibition probably represents one of many potential causes of PD, but it alerts us to the dangers of such substances in the environment and the need to identify genetically susceptible populations. When vulnerable individuals become known, perhaps they should stay out of the garden.
A recent paper by Greenamyre and colleagues1 showed the selective destruction of nigral dopaminergic neurones in rats infused intravenously with a low dose of the herbicide rotenone. The study raises many important questions. The ability of rotenone to target nigral cells and produce a pattern of cell death that is reminiscent of Parkinson’s disease (PD) accompanied by the appearance of Lewy body-like inclusions might be telling, as far as the pathogenesis of PD is concerned. Others have previously carried out similar studies but failed to see selective nigral damage as a result of systemic rotenone infusion, because higher doses induce nonspecific brain damage2. Rotenone is a well characterized and commonly used inhibitor of complex I of the mitochondrial respiratory chain. However, it is also a herbicide commonly used by gardeners as the active ingredient of derris dust or liquid preparations of derris described as ‘natural herbicide’, which are commonly found on the shelves of garden centres. Rotenone is not the first complex I inhibitor to be associated with selective nigral neurone degeneration, as this is the proposed mechanism of action of MPP+, the active metabolite of MPTP (Ref. 3). However, there are differences: rotenone causes ubiquitous complex I inhibition but degeneration only in the
substantia nigra (and to some degree in the locus coeruleus), whereas MPP+ appears to be more targeted – using uptake mechanisms to enter dopaminergic nerve terminals. However, neither toxin kills neurones in the adjacent dopaminergic ventral tegmental area. Greenamyre’s study therefore highlights the likelihood that a selective vulnerability of nigral neurones to complex I inhibition could be the key factor. Indeed, Greenamyre et al. point out that the actions of rotenone are not associated with inhibition of mitochondrial respiration, and hence ATP production, but rather might be due to the onset of oxidative stress, which is known to be associated with nigral cell death in sporadic PD (Ref. 4). But what is still missing, and is crucial to the mechanisms that underlie nigral degeneration, is the reason for the vulnerability of nigral cells to toxic processes, such as complex I inhibition. Greenamyre et al. underline this vulnerability but do not explain it. Another important facet of Greenamyre’s paper is the finding of fibrillar cytoplasmic inclusions that are immunoreactive for ubiquitin and α-synuclein in nigral dopaminergic cells. These inclusions have been likened to Lewy bodies, which are deemed to be the pathological hallmark of PD, although they do occur in other degenerative diseases, such as dementia of the Lewy
body type. The formation of inclusions in response to rotenone exposure could indicate a similar toxic mechanism to the pathological process occurring in PD itself. In contrast, after 6hydroxydopamine- or MPTP- (or MPP+) induced lesions of nigral cells, similar inclusions have not been reported, although how closely we have looked using new techniques could be questioned. Inclusions that closely resemble those found after rotenone exposure also occur in cells that overexpress the mutant α-synucleins associated with some cases of familial PD (Ref. 5). In these reports, inclusion formation has been associated with the decreased proteolysis that leads to aggregation and protein deposition. Why inclusion formation should also occur in response to rotenone exposure in Greenamyre’s study is not clear. If oxidative stress does ensue, then either the presence of oxidized proteins or oxidative damage to the proteasome might also impair protein degradation and induce the formation of inclusion bodies6. Greenamyre’s paper also raises the extension of the findings with rotenone to other pesticides. Previously, epidemiology studies have suggested an association between pesticide use and the prevalence of PD (Ref. 7), and there have been reports of increased levels of pesticide residues in the substantia nigra of individuals with PD compared with control populations. Indeed, some synthetic pesticides are also complex I inhibitors, at least in vitro8, but to date there have been no convincing mechanistic studies or investigations similar to Greenamyre’s work to show a clear association of nigral degeneration with pesticide exposure. One outcome of Greenamyre’s paper could be the realization that we need to look at other commonly used pesticides in a similar manner. In addition, while Greenamyre’s studies extended to infusions of rotenone over periods in excess of five weeks, it is
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(00)01789-6
246
Research Update
now imperative to examine the effects of long-term low-dose rotenone exposure, and to extend these studies to primates to examine the relevance of this work to humans. However, it is worth remembering that James Parkinson described PD long before the pesticide era commenced in the 1940s–1950s. So, they cannot be the sole cause of PD. Rather, we should also consider the relevance of exposure to other natural products that act in a similar manner to rotenone and MPP+: through inhibition of complex I. For example, other investigators have shown that a variety of isoquinolines and β-carbolines also inhibit complex I, and some of these are toxic to dopaminergic neurones both in vitro and in vivo9. But such reports have never been viewed with the seriousness they demand, despite the common occurrence of isoquinolines and β-carbolines in food and drink. Hopefully Greenamyre’s paper will galvanize us into determining the nature and number of such potentially toxic molecules to which we are continually exposed. Complex I inhibition in the substantia nigra (and also in platelets) is a feature of cell death in idiopathic PD (Ref. 10). No toxin has so far been detected in the substantia nigra that would explain the biochemical change observed. Indeed, the construction of cybrids using mitochondrial DNA from the platelets of individuals with PD has suggested that complex I inhibition is a genetic defect11, although no consistent alterations in the encoding of complex I have been uncovered in nigra in sporadic PD. One family with PD is associated with a maternally inherited complex I deficiency12 but this does not appear to be a common finding, even in the rare familial form of the illness. Interestingly, the complex I defect (30–40% inhibition) found in homogenates of nigral tissue in PD is too big to be restricted to nigral dopaminergic neurones, which make up only 1–2% of all cells in this brain area. The current suggestion is that complex I inhibition also involves glial cells and it would have been interesting in Greenamyre’s study to look at the role glia play in the actions of rotenone. Importantly, however, only a proportion of individuals dying from PD show complex I inhibition in the substantia nigra and the majority have normal http://tins.trends.com
TRENDS in Neurosciences Vol.24 No.5 May 2001
complex I function. This raises several issues related to Greenamyre’s findings. First, 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. Second, the lack of complex I inhibition in many patients raises the spectre of a range of causes of PD that are associated with distinct subsets of patients: this is supported by the vulnerability of substantia nigra to many toxic insults. Third, in those individuals who have a complex I defect (which appears to be inherited), additional exposure to complex I inhibitors such as rotenone, or indeed other toxins, might precipitates the onset of nigral cell death. The latter raises the concept of the susceptibility of the individual to toxin action and the role of susceptibility genes in PD. ‘It is possible that the susceptibility of an individual to the effects of rotenone and other pesticides is determined …’ genetically…
The current view of sporadic PD is that it is caused by a combination of genetic and environmental factors: the work of Greenamyre would support the contribution that exogenous toxins might make. It is likely that a variety of different toxic insults can contribute to nigral pathology in PD, and that complex I inhibition represents one such factor. Genetic susceptibility to the actions of enviromental toxins is also likely, although no gene defects have so far been identified. It is possible that the susceptibility of an individual to the effects of rotenone and other pesticides is determined genetically, because not all those who are exposed develop PD. Indeed, if in the future such vulnerable populations can be identified, then perhaps some of us should stay out of the garden. References 1 Betarbet, R. et al. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci 3, 1301–1306 2 Ferrante, R.J. et al. (1997) Systemic administration of rotenone produces selective damage in the striatum and globus pallidus but not substantia nigra. Brain Res. 753, 157–162 3 Nicklas, W.J. and Heikkila, R.E. (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenylpyridine, a metabolite of the
4
5
6
7
8
9
10
11
12
neurotoxin, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine. Life Sci. 36, 2503–2508 Jenner, P. and Olanow, C.W. (1998) Understanding cell death in Parkinson’s disease. Ann. Neurol. 44, S72–S84 Ostrerova, N. et al. (2000) The A53T alphasynuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048–6054 Halliwell, B. and Jenner, P. (1998) Impaired clearance of oxidised proteins in neurodegenerative disease. Lancet 351, 1510 Gorell, J.M. et al. (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water and rural living. Neurology 50, 1346–1350 Degli Eposti, M. (1998) Inhibitors of NADHubiquinone reductase: an overview. Biochim. Biophys. Acta 1364, 222–235 McNaught, K.St.P. (1998) Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson’s disease. Biochem. Pharmacol. 56, 921–933 Schapira, A.H.V. et al. (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J. Neurochem. 54, 823–827 Swerdlow, R.H. et al. (1996) Origin and functional consequences of the complex I defect in Parkinson’s disease. Ann. Neurol. 40, 663–671 Swerdlow, R.H. et al. (1998) Matrilineal inheritance of complex I dysfunction in a multigeneration Parkinson’s disease family. Ann. Neurol. 44, 873–881
Peter Jenner King’s College London, Manresa Road, London, UK SW3 6LX. e-mail: [email protected]
Book Reviews Publishers Trends in Neurosciences welcomes books for review. Please send books or book details to: Dr Siân Lewis, Editor, Trends in Neurosciences, 84 Theobald’s Road, London, UK WC1X 8RR.
Reviewers If you are interested in reviewing books for Trends in Neurosciences, please contact the Editor, Dr Siân Lewis, with your suggestions. Tel: +44 (0)20 7611 4400 Fax: +44 (0)20 7611 4470 E-mail: [email protected]
TRENDS in Neurosciences Vol.24 No.5 May 2001
245
Research News
Parkinson’s disease, pesticides and mitochondrial dysfunction Peter Jenner Selective nigral degeneration with inclusion formation provoked by systemic administration of the herbicide rotenone, through inhibition of complex I, raises the question of pesticide exposure and environmental factors in general, as a cause of Parkinson’s disease (PD). Toxininduced complex I inhibition probably represents one of many potential causes of PD, but it alerts us to the dangers of such substances in the environment and the need to identify genetically susceptible populations. When vulnerable individuals become known, perhaps they should stay out of the garden.
A recent paper by Greenamyre and colleagues1 showed the selective destruction of nigral dopaminergic neurones in rats infused intravenously with a low dose of the herbicide rotenone. The study raises many important questions. The ability of rotenone to target nigral cells and produce a pattern of cell death that is reminiscent of Parkinson’s disease (PD) accompanied by the appearance of Lewy body-like inclusions might be telling, as far as the pathogenesis of PD is concerned. Others have previously carried out similar studies but failed to see selective nigral damage as a result of systemic rotenone infusion, because higher doses induce nonspecific brain damage2. Rotenone is a well characterized and commonly used inhibitor of complex I of the mitochondrial respiratory chain. However, it is also a herbicide commonly used by gardeners as the active ingredient of derris dust or liquid preparations of derris described as ‘natural herbicide’, which are commonly found on the shelves of garden centres. Rotenone is not the first complex I inhibitor to be associated with selective nigral neurone degeneration, as this is the proposed mechanism of action of MPP+, the active metabolite of MPTP (Ref. 3). However, there are differences: rotenone causes ubiquitous complex I inhibition but degeneration only in the
substantia nigra (and to some degree in the locus coeruleus), whereas MPP+ appears to be more targeted – using uptake mechanisms to enter dopaminergic nerve terminals. However, neither toxin kills neurones in the adjacent dopaminergic ventral tegmental area. Greenamyre’s study therefore highlights the likelihood that a selective vulnerability of nigral neurones to complex I inhibition could be the key factor. Indeed, Greenamyre et al. point out that the actions of rotenone are not associated with inhibition of mitochondrial respiration, and hence ATP production, but rather might be due to the onset of oxidative stress, which is known to be associated with nigral cell death in sporadic PD (Ref. 4). But what is still missing, and is crucial to the mechanisms that underlie nigral degeneration, is the reason for the vulnerability of nigral cells to toxic processes, such as complex I inhibition. Greenamyre et al. underline this vulnerability but do not explain it. Another important facet of Greenamyre’s paper is the finding of fibrillar cytoplasmic inclusions that are immunoreactive for ubiquitin and α-synuclein in nigral dopaminergic cells. These inclusions have been likened to Lewy bodies, which are deemed to be the pathological hallmark of PD, although they do occur in other degenerative diseases, such as dementia of the Lewy
body type. The formation of inclusions in response to rotenone exposure could indicate a similar toxic mechanism to the pathological process occurring in PD itself. In contrast, after 6hydroxydopamine- or MPTP- (or MPP+) induced lesions of nigral cells, similar inclusions have not been reported, although how closely we have looked using new techniques could be questioned. Inclusions that closely resemble those found after rotenone exposure also occur in cells that overexpress the mutant α-synucleins associated with some cases of familial PD (Ref. 5). In these reports, inclusion formation has been associated with the decreased proteolysis that leads to aggregation and protein deposition. Why inclusion formation should also occur in response to rotenone exposure in Greenamyre’s study is not clear. If oxidative stress does ensue, then either the presence of oxidized proteins or oxidative damage to the proteasome might also impair protein degradation and induce the formation of inclusion bodies6. Greenamyre’s paper also raises the extension of the findings with rotenone to other pesticides. Previously, epidemiology studies have suggested an association between pesticide use and the prevalence of PD (Ref. 7), and there have been reports of increased levels of pesticide residues in the substantia nigra of individuals with PD compared with control populations. Indeed, some synthetic pesticides are also complex I inhibitors, at least in vitro8, but to date there have been no convincing mechanistic studies or investigations similar to Greenamyre’s work to show a clear association of nigral degeneration with pesticide exposure. One outcome of Greenamyre’s paper could be the realization that we need to look at other commonly used pesticides in a similar manner. In addition, while Greenamyre’s studies extended to infusions of rotenone over periods in excess of five weeks, it is
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(00)01789-6
246
Research Update
now imperative to examine the effects of long-term low-dose rotenone exposure, and to extend these studies to primates to examine the relevance of this work to humans. However, it is worth remembering that James Parkinson described PD long before the pesticide era commenced in the 1940s–1950s. So, they cannot be the sole cause of PD. Rather, we should also consider the relevance of exposure to other natural products that act in a similar manner to rotenone and MPP+: through inhibition of complex I. For example, other investigators have shown that a variety of isoquinolines and β-carbolines also inhibit complex I, and some of these are toxic to dopaminergic neurones both in vitro and in vivo9. But such reports have never been viewed with the seriousness they demand, despite the common occurrence of isoquinolines and β-carbolines in food and drink. Hopefully Greenamyre’s paper will galvanize us into determining the nature and number of such potentially toxic molecules to which we are continually exposed. Complex I inhibition in the substantia nigra (and also in platelets) is a feature of cell death in idiopathic PD (Ref. 10). No toxin has so far been detected in the substantia nigra that would explain the biochemical change observed. Indeed, the construction of cybrids using mitochondrial DNA from the platelets of individuals with PD has suggested that complex I inhibition is a genetic defect11, although no consistent alterations in the encoding of complex I have been uncovered in nigra in sporadic PD. One family with PD is associated with a maternally inherited complex I deficiency12 but this does not appear to be a common finding, even in the rare familial form of the illness. Interestingly, the complex I defect (30–40% inhibition) found in homogenates of nigral tissue in PD is too big to be restricted to nigral dopaminergic neurones, which make up only 1–2% of all cells in this brain area. The current suggestion is that complex I inhibition also involves glial cells and it would have been interesting in Greenamyre’s study to look at the role glia play in the actions of rotenone. Importantly, however, only a proportion of individuals dying from PD show complex I inhibition in the substantia nigra and the majority have normal http://tins.trends.com
TRENDS in Neurosciences Vol.24 No.5 May 2001
complex I function. This raises several issues related to Greenamyre’s findings. First, 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. Second, the lack of complex I inhibition in many patients raises the spectre of a range of causes of PD that are associated with distinct subsets of patients: this is supported by the vulnerability of substantia nigra to many toxic insults. Third, in those individuals who have a complex I defect (which appears to be inherited), additional exposure to complex I inhibitors such as rotenone, or indeed other toxins, might precipitates the onset of nigral cell death. The latter raises the concept of the susceptibility of the individual to toxin action and the role of susceptibility genes in PD. ‘It is possible that the susceptibility of an individual to the effects of rotenone and other pesticides is determined …’ genetically…
The current view of sporadic PD is that it is caused by a combination of genetic and environmental factors: the work of Greenamyre would support the contribution that exogenous toxins might make. It is likely that a variety of different toxic insults can contribute to nigral pathology in PD, and that complex I inhibition represents one such factor. Genetic susceptibility to the actions of enviromental toxins is also likely, although no gene defects have so far been identified. It is possible that the susceptibility of an individual to the effects of rotenone and other pesticides is determined genetically, because not all those who are exposed develop PD. Indeed, if in the future such vulnerable populations can be identified, then perhaps some of us should stay out of the garden. References 1 Betarbet, R. et al. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci 3, 1301–1306 2 Ferrante, R.J. et al. (1997) Systemic administration of rotenone produces selective damage in the striatum and globus pallidus but not substantia nigra. Brain Res. 753, 157–162 3 Nicklas, W.J. and Heikkila, R.E. (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenylpyridine, a metabolite of the
4
5
6
7
8
9
10
11
12
neurotoxin, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine. Life Sci. 36, 2503–2508 Jenner, P. and Olanow, C.W. (1998) Understanding cell death in Parkinson’s disease. Ann. Neurol. 44, S72–S84 Ostrerova, N. et al. (2000) The A53T alphasynuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048–6054 Halliwell, B. and Jenner, P. (1998) Impaired clearance of oxidised proteins in neurodegenerative disease. Lancet 351, 1510 Gorell, J.M. et al. (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water and rural living. Neurology 50, 1346–1350 Degli Eposti, M. (1998) Inhibitors of NADHubiquinone reductase: an overview. Biochim. Biophys. Acta 1364, 222–235 McNaught, K.St.P. (1998) Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson’s disease. Biochem. Pharmacol. 56, 921–933 Schapira, A.H.V. et al. (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J. Neurochem. 54, 823–827 Swerdlow, R.H. et al. (1996) Origin and functional consequences of the complex I defect in Parkinson’s disease. Ann. Neurol. 40, 663–671 Swerdlow, R.H. et al. (1998) Matrilineal inheritance of complex I dysfunction in a multigeneration Parkinson’s disease family. Ann. Neurol. 44, 873–881
Peter Jenner King’s College London, Manresa Road, London, UK SW3 6LX. e-mail: [email protected]
Book Reviews Publishers Trends in Neurosciences welcomes books for review. Please send books or book details to: Dr Siân Lewis, Editor, Trends in Neurosciences, 84 Theobald’s Road, London, UK WC1X 8RR.
Reviewers If you are interested in reviewing books for Trends in Neurosciences, please contact the Editor, Dr Siân Lewis, with your suggestions. Tel: +44 (0)20 7611 4400 Fax: +44 (0)20 7611 4470 E-mail: [email protected]