Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers

Ye Zhao, Gayathri Perera, Junko Takahashi-Fujigasaki, Deborah C Mash, Jean Paul G. Vonsattel, Akiko Uchino, Kazuko Hasegawa, R. Jeremy Nichols, Janice L. Holton, Shigeo Murayama, Nicolas Dzamko, Glenda M. Halliday

Research output: Contribution to journalArticle

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Abstract

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-Associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-Associated Parkinson's disease brain.

Original languageEnglish (US)
Pages (from-to)486-495
Number of pages10
JournalBrain
Volume141
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Leucine
Phosphotransferases
Mutation
Brain
Parkinson Disease
Protein Kinases
Glucosylceramidase
IGF Type 2 Receptor
Proteins
Hydrolases
Protein Transport
Missense Mutation
Cations

Keywords

  • alpha-synuclein
  • kinase inhibitor
  • LRRK2
  • Parkinson's disease
  • retromer

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Zhao, Y., Perera, G., Takahashi-Fujigasaki, J., Mash, D. C., Vonsattel, J. P. G., Uchino, A., ... Halliday, G. M. (2018). Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers. Brain, 141(2), 486-495. https://doi.org/10.1093/brain/awx344

Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers. / Zhao, Ye; Perera, Gayathri; Takahashi-Fujigasaki, Junko; Mash, Deborah C; Vonsattel, Jean Paul G.; Uchino, Akiko; Hasegawa, Kazuko; Jeremy Nichols, R.; Holton, Janice L.; Murayama, Shigeo; Dzamko, Nicolas; Halliday, Glenda M.

In: Brain, Vol. 141, No. 2, 01.02.2018, p. 486-495.

Research output: Contribution to journalArticle

Zhao, Y, Perera, G, Takahashi-Fujigasaki, J, Mash, DC, Vonsattel, JPG, Uchino, A, Hasegawa, K, Jeremy Nichols, R, Holton, JL, Murayama, S, Dzamko, N & Halliday, GM 2018, 'Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers', Brain, vol. 141, no. 2, pp. 486-495. https://doi.org/10.1093/brain/awx344
Zhao Y, Perera G, Takahashi-Fujigasaki J, Mash DC, Vonsattel JPG, Uchino A et al. Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers. Brain. 2018 Feb 1;141(2):486-495. https://doi.org/10.1093/brain/awx344
Zhao, Ye ; Perera, Gayathri ; Takahashi-Fujigasaki, Junko ; Mash, Deborah C ; Vonsattel, Jean Paul G. ; Uchino, Akiko ; Hasegawa, Kazuko ; Jeremy Nichols, R. ; Holton, Janice L. ; Murayama, Shigeo ; Dzamko, Nicolas ; Halliday, Glenda M. / Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers. In: Brain. 2018 ; Vol. 141, No. 2. pp. 486-495.
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abstract = "Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-Associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1{\%} of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-Associated Parkinson's disease brain.",
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