LRRK2 activation in idiopathic Parkinson's disease

Roberto Di Maio; Eric K. Hoffman; Emily M. Rocha; Matthew T. Keeney; Laurie H. Sanders; Briana R. De Miranda; Alevtina Zharikov; Amber Van Laar; Antonia F. Stepan; Thomas A. Lanz; Julia K. Kofler; Edward A. Burton; Dario R. Alessi; Teresa G. Hastings; J. Timothy Greenamyre

doi:10.1126/scitranslmed.aar5429

LRRK2 activation in idiopathic Parkinson's disease

Roberto Di Maio, Eric K. Hoffman, Emily M. Rocha, Matthew T. Keeney, Laurie H. Sanders, Briana R. De Miranda, Alevtina Zharikov, Amber Van Laar, Antonia F. Stepan, Thomas A. Lanz, Julia K. Kofler, Edward A. Burton, Dario R. Alessi, Teresa G. Hastings, J. Timothy Greenamyre (Lead / Corresponding author)

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Abstract

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). However, a potential role of wild-type LRRK2 in idiopathic PD (iPD) remains unclear. Here, we developed proximity ligation assays to assess Ser1292 phosphorylation of LRRK2 and, separately, the dissociation of 14-3-3 proteins from LRRK2. Using these proximity ligation assays, we show that wild-type LRRK2 kinase activity was selectively enhanced in substantia nigra dopamine neurons in postmortem brain tissue from patients with iPD and in two different rat models of the disease. We show that this occurred through an oxidative mechanism, resulting in phosphorylation of the LRRK2 substrate Rab10 and other downstream consequences including abnormalities in mitochondrial protein import and lysosomal function. Our study suggests that, independent of mutations, wild-type LRRK2 plays a role in iPD. LRRK2 kinase inhibitors may therefore be useful for treating patients with iPD who do not carry LRRK2 mutations.

Original language	English
Article number	eaar5429
Pages (from-to)	1-12
Number of pages	12
Journal	Science Translational Medicine
Volume	10
Issue number	451
DOIs	https://doi.org/10.1126/scitranslmed.aar5429
Publication status	Published - 25 Jul 2018

ASJC Scopus subject areas

General Medicine

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10.1126/scitranslmed.aar5429

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This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on [Volume number and date], DOI: [insert DOI number].
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Di Maio, R., Hoffman, E. K., Rocha, E. M., Keeney, M. T., Sanders, L. H., De Miranda, B. R., Zharikov, A., Van Laar, A., Stepan, A. F., Lanz, T. A., Kofler, J. K., Burton, E. A., Alessi, D. R., Hastings, T. G., & Timothy Greenamyre, J. (2018). LRRK2 activation in idiopathic Parkinson's disease. Science Translational Medicine, 10(451), 1-12. Article eaar5429. https://doi.org/10.1126/scitranslmed.aar5429

@article{b353f18498784dfcb6de8b26fc9373a0,

title = "LRRK2 activation in idiopathic Parkinson's disease",

abstract = "Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). However, a potential role of wild-type LRRK2 in idiopathic PD (iPD) remains unclear. Here, we developed proximity ligation assays to assess Ser1292 phosphorylation of LRRK2 and, separately, the dissociation of 14-3-3 proteins from LRRK2. Using these proximity ligation assays, we show that wild-type LRRK2 kinase activity was selectively enhanced in substantia nigra dopamine neurons in postmortem brain tissue from patients with iPD and in two different rat models of the disease. We show that this occurred through an oxidative mechanism, resulting in phosphorylation of the LRRK2 substrate Rab10 and other downstream consequences including abnormalities in mitochondrial protein import and lysosomal function. Our study suggests that, independent of mutations, wild-type LRRK2 plays a role in iPD. LRRK2 kinase inhibitors may therefore be useful for treating patients with iPD who do not carry LRRK2 mutations.",

author = "{Di Maio}, Roberto and Hoffman, {Eric K.} and Rocha, {Emily M.} and Keeney, {Matthew T.} and Sanders, {Laurie H.} and {De Miranda}, {Briana R.} and Alevtina Zharikov and {Van Laar}, Amber and Stepan, {Antonia F.} and Lanz, {Thomas A.} and Kofler, {Julia K.} and Burton, {Edward A.} and Alessi, {Dario R.} and Hastings, {Teresa G.} and {Timothy Greenamyre}, J.",

note = "Funding: This work was supported by research grants from the National Institutes of Health (NS100744, R21ES027470, NS095387, AG005133), the Blechman Foundation, the American Parkinson Disease Association, and friends and family of Sean Logan. The brain bank has received support from the University of Pittsburgh Brain Institute. Work in the Alessi lab on LRRK2 is supported by the Michael J. Fox Foundation for Parkinson's research [grant number 6986]; the Medical Research Council [grant number MC_UU_12016/2] and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer‐Ingelheim, GlaxoSmithKline, and Merck KGaA, to D.R.A.). Competing interests: Greenamyre briefly held an advisory position at Pfizer. Otherwise, the authors declare that they have no competing financial interests. Data and Materials Availability: JTG received the PF-360 compound from Pfizer and is not authorized to distribute it.",

year = "2018",

month = jul,

day = "25",

doi = "10.1126/scitranslmed.aar5429",

language = "English",

volume = "10",

pages = "1--12",

journal = "Science Translational Medicine",

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publisher = "American Association for the Advancement of Science",

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Di Maio, R, Hoffman, EK, Rocha, EM, Keeney, MT, Sanders, LH, De Miranda, BR, Zharikov, A, Van Laar, A, Stepan, AF, Lanz, TA, Kofler, JK, Burton, EA, Alessi, DR, Hastings, TG & Timothy Greenamyre, J 2018, 'LRRK2 activation in idiopathic Parkinson's disease', Science Translational Medicine, vol. 10, no. 451, eaar5429, pp. 1-12. https://doi.org/10.1126/scitranslmed.aar5429

TY - JOUR

T1 - LRRK2 activation in idiopathic Parkinson's disease

AU - Di Maio, Roberto

AU - Hoffman, Eric K.

AU - Rocha, Emily M.

AU - Keeney, Matthew T.

AU - Sanders, Laurie H.

AU - De Miranda, Briana R.

AU - Zharikov, Alevtina

AU - Van Laar, Amber

AU - Stepan, Antonia F.

AU - Lanz, Thomas A.

AU - Kofler, Julia K.

AU - Burton, Edward A.

AU - Alessi, Dario R.

AU - Hastings, Teresa G.

AU - Timothy Greenamyre, J.

N1 - Funding: This work was supported by research grants from the National Institutes of Health (NS100744, R21ES027470, NS095387, AG005133), the Blechman Foundation, the American Parkinson Disease Association, and friends and family of Sean Logan. The brain bank has received support from the University of Pittsburgh Brain Institute. Work in the Alessi lab on LRRK2 is supported by the Michael J. Fox Foundation for Parkinson's research [grant number 6986]; the Medical Research Council [grant number MC_UU_12016/2] and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer‐Ingelheim, GlaxoSmithKline, and Merck KGaA, to D.R.A.). Competing interests: Greenamyre briefly held an advisory position at Pfizer. Otherwise, the authors declare that they have no competing financial interests. Data and Materials Availability: JTG received the PF-360 compound from Pfizer and is not authorized to distribute it.

PY - 2018/7/25

Y1 - 2018/7/25

N2 - Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). However, a potential role of wild-type LRRK2 in idiopathic PD (iPD) remains unclear. Here, we developed proximity ligation assays to assess Ser1292 phosphorylation of LRRK2 and, separately, the dissociation of 14-3-3 proteins from LRRK2. Using these proximity ligation assays, we show that wild-type LRRK2 kinase activity was selectively enhanced in substantia nigra dopamine neurons in postmortem brain tissue from patients with iPD and in two different rat models of the disease. We show that this occurred through an oxidative mechanism, resulting in phosphorylation of the LRRK2 substrate Rab10 and other downstream consequences including abnormalities in mitochondrial protein import and lysosomal function. Our study suggests that, independent of mutations, wild-type LRRK2 plays a role in iPD. LRRK2 kinase inhibitors may therefore be useful for treating patients with iPD who do not carry LRRK2 mutations.

AB - Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). However, a potential role of wild-type LRRK2 in idiopathic PD (iPD) remains unclear. Here, we developed proximity ligation assays to assess Ser1292 phosphorylation of LRRK2 and, separately, the dissociation of 14-3-3 proteins from LRRK2. Using these proximity ligation assays, we show that wild-type LRRK2 kinase activity was selectively enhanced in substantia nigra dopamine neurons in postmortem brain tissue from patients with iPD and in two different rat models of the disease. We show that this occurred through an oxidative mechanism, resulting in phosphorylation of the LRRK2 substrate Rab10 and other downstream consequences including abnormalities in mitochondrial protein import and lysosomal function. Our study suggests that, independent of mutations, wild-type LRRK2 plays a role in iPD. LRRK2 kinase inhibitors may therefore be useful for treating patients with iPD who do not carry LRRK2 mutations.

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U2 - 10.1126/scitranslmed.aar5429

DO - 10.1126/scitranslmed.aar5429

M3 - Article

C2 - 30045977

AN - SCOPUS:85050770401

SN - 1946-6234

VL - 10

SP - 1

EP - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 451

M1 - eaar5429

ER -

LRRK2 activation in idiopathic Parkinson's disease

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Towards a Unifying Theory of Parkinson's Disease - Investigation of the Biochemical and Genetic Role of Rab GTPases (joint with German Centre for Neurodegenerative Diseases)

Alessi, Dario

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LRRK2 activation in idiopathic Parkinson's disease

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Towards a Unifying Theory of Parkinson's Disease - Investigation of the Biochemical and Genetic Role of Rab GTPases (joint with German Centre for Neurodegenerative Diseases)

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Alessi, Dario

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