Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

Lena F. Burbulla; Pingping Song; Joseph R. Mazzulli; Enrico Zampese; Yvette C. Wong; Sohee Jeon; David P. Santos; Judith Blanz; Carolin D. Obermaier; Chelsee Strojny; Jeffrey N. Savas; Evangelos Kiskinis; Xiaoxi Zhuang; Rejko Krüger; D. James Surmeier; Dimitri Krainc

doi:10.1126/science.aam9080

Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

Lena F. Burbulla, Pingping Song, Joseph R. Mazzulli, Enrico Zampese, Yvette C. Wong, Sohee Jeon, David P. Santos, Judith Blanz, Carolin D. Obermaier, Chelsee Strojny, Jeffrey N. Savas, Evangelos Kiskinis, Xiaoxi Zhuang, Rejko Krüger, D. James Surmeier, Dimitri Krainc^*

^*Corresponding author for this work

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Abstract

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson’s disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and a-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or a-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.

Original language	English (US)
Pages (from-to)	1255-1261
Number of pages	7
Journal	Science
Volume	357
Issue number	6357
DOIs	https://doi.org/10.1126/science.aam9080
State	Published - Sep 22 2017

Funding

We are grateful to D. Sulzer, E. V. Mosharov, J. W. Shim, G. Caraveo, and J. Zheng for helpful discussions and suggestions. We thank the Northwestern Stem Cell Core Facility for the generation of mouse iPSC lines (supported by P30 NS081774). We are grateful to K. Hamada as well as M. K. V. Suresh for technical assistance and C. Leong for help with the assessment of off-target gene editing in the CRISPR-edited lines. The mito-roGFP construct was a gift from P. Schumacker (Northwestern University). This work was supported by NIH (grants R01NS076054 to D.K., NS047085 to D.J.S., R01NS092823 to J.R.M., R00DC013805-02 to J.N.S., and T32NS041234 and F32NS101778 to Y.C.W.); The JPB Foundation and The Michael J. Fox and IDP Foundations to D.J.S.; German Academic Exchange Service to L.F.B.; Les Turner ALS Foundation, Target ALS, and MDA to E.K.; and the German Research Council grant KR2119/8-1 and the Fond National de Recherche PEARL program grant FNR/P13/6682797 to R.K. All data necessary to support this paper’s conclusions are available in the supplementary materials.

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Burbulla, L. F., Song, P., Mazzulli, J. R., Zampese, E., Wong, Y. C., Jeon, S., Santos, D. P., Blanz, J., Obermaier, C. D., Strojny, C., Savas, J. N., Kiskinis, E., Zhuang, X., Krüger, R., Surmeier, D. J., & Krainc, D. (2017). Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science, 357(6357), 1255-1261. https://doi.org/10.1126/science.aam9080

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abstract = "Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson{\textquoteright}s disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and a-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or a-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.",

author = "Burbulla, {Lena F.} and Pingping Song and Mazzulli, {Joseph R.} and Enrico Zampese and Wong, {Yvette C.} and Sohee Jeon and Santos, {David P.} and Judith Blanz and Obermaier, {Carolin D.} and Chelsee Strojny and Savas, {Jeffrey N.} and Evangelos Kiskinis and Xiaoxi Zhuang and Rejko Kr{\"u}ger and Surmeier, {D. James} and Dimitri Krainc",

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doi = "10.1126/science.aam9080",

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Burbulla, LF, Song, P , Mazzulli, JR, Zampese, E, Wong, YC, Jeon, S, Santos, DP, Blanz, J, Obermaier, CD, Strojny, C, Savas, JN , Kiskinis, E, Zhuang, X, Krüger, R, Surmeier, DJ & Krainc, D 2017, 'Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease', Science, vol. 357, no. 6357, pp. 1255-1261. https://doi.org/10.1126/science.aam9080

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AU - Burbulla, Lena F.

AU - Song, Pingping

AU - Mazzulli, Joseph R.

AU - Zampese, Enrico

AU - Wong, Yvette C.

AU - Jeon, Sohee

AU - Santos, David P.

AU - Blanz, Judith

AU - Obermaier, Carolin D.

AU - Strojny, Chelsee

AU - Savas, Jeffrey N.

AU - Kiskinis, Evangelos

AU - Zhuang, Xiaoxi

AU - Krüger, Rejko

AU - Surmeier, D. James

AU - Krainc, Dimitri

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AB - Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson’s disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and a-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or a-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.

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Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

Abstract

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