Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

Arthur G. Fitzmaurice, Shannon L. Rhodes, Aaron Lulla, Niall P. Murphy, Hoa A. Lam, Kelley C. O'Donnell, Lisa Barnhill, John E. Casida, Myles Cockburn, Alvaro Sagasti, Mark C. Stahl, Nigel T. Maidment, Beate Ritz, Jeff M. Bronstein

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Abstract

Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associatedwith PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii ) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi ) In vitro cell loss was attenuated by reducing DOPAL formation. (vii ) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

Original languageEnglish (US)
Pages (from-to)636-641
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number2
DOIs
StatePublished - Jan 8 2013

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Aldehyde Dehydrogenase
Benomyl
Parkinson Disease
Dopaminergic Neurons
sulfoxide
Dopamine
Thiocarbamates
Zebrafish
Substantia Nigra
Pesticides
Neurodegenerative Diseases
Epidemiology
Homeostasis
Neurons

All Science Journal Classification (ASJC) codes

  • General

Cite this

Fitzmaurice, A. G., Rhodes, S. L., Lulla, A., Murphy, N. P., Lam, H. A., O'Donnell, K. C., ... Bronstein, J. M. (2013). Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proceedings of the National Academy of Sciences of the United States of America, 110(2), 636-641. https://doi.org/10.1073/pnas.1220399110
Fitzmaurice, Arthur G. ; Rhodes, Shannon L. ; Lulla, Aaron ; Murphy, Niall P. ; Lam, Hoa A. ; O'Donnell, Kelley C. ; Barnhill, Lisa ; Casida, John E. ; Cockburn, Myles ; Sagasti, Alvaro ; Stahl, Mark C. ; Maidment, Nigel T. ; Ritz, Beate ; Bronstein, Jeff M. / Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 2. pp. 636-641.
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abstract = "Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associatedwith PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii ) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi ) In vitro cell loss was attenuated by reducing DOPAL formation. (vii ) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.",
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Fitzmaurice, AG, Rhodes, SL, Lulla, A, Murphy, NP, Lam, HA, O'Donnell, KC, Barnhill, L, Casida, JE, Cockburn, M, Sagasti, A, Stahl, MC, Maidment, NT, Ritz, B & Bronstein, JM 2013, 'Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 2, pp. 636-641. https://doi.org/10.1073/pnas.1220399110

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. / Fitzmaurice, Arthur G.; Rhodes, Shannon L.; Lulla, Aaron; Murphy, Niall P.; Lam, Hoa A.; O'Donnell, Kelley C.; Barnhill, Lisa; Casida, John E.; Cockburn, Myles; Sagasti, Alvaro; Stahl, Mark C.; Maidment, Nigel T.; Ritz, Beate; Bronstein, Jeff M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 2, 08.01.2013, p. 636-641.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

AU - Fitzmaurice, Arthur G.

AU - Rhodes, Shannon L.

AU - Lulla, Aaron

AU - Murphy, Niall P.

AU - Lam, Hoa A.

AU - O'Donnell, Kelley C.

AU - Barnhill, Lisa

AU - Casida, John E.

AU - Cockburn, Myles

AU - Sagasti, Alvaro

AU - Stahl, Mark C.

AU - Maidment, Nigel T.

AU - Ritz, Beate

AU - Bronstein, Jeff M.

PY - 2013/1/8

Y1 - 2013/1/8

N2 - Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associatedwith PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii ) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi ) In vitro cell loss was attenuated by reducing DOPAL formation. (vii ) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

AB - Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associatedwith PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii ) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi ) In vitro cell loss was attenuated by reducing DOPAL formation. (vii ) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

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