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 language | English (US) |
|---|---|
| Pages (from-to) | 486-495 |
| Number of pages | 10 |
| Journal | Brain |
| Volume | 141 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2018 |
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Keywords
- alpha-synuclein
- kinase inhibitor
- LRRK2
- Parkinson's disease
- retromer
ASJC Scopus subject areas
- Clinical Neurology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers
AU - Zhao, Ye
AU - Perera, Gayathri
AU - Takahashi-Fujigasaki, Junko
AU - Mash, Deborah C
AU - Vonsattel, Jean Paul G.
AU - Uchino, Akiko
AU - Hasegawa, Kazuko
AU - Jeremy Nichols, R.
AU - Holton, Janice L.
AU - Murayama, Shigeo
AU - Dzamko, Nicolas
AU - Halliday, Glenda M.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
KW - alpha-synuclein
KW - kinase inhibitor
KW - LRRK2
KW - Parkinson's disease
KW - retromer
UR - http://www.scopus.com/inward/record.url?scp=85041694443&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041694443&partnerID=8YFLogxK
U2 - 10.1093/brain/awx344
DO - 10.1093/brain/awx344
M3 - Article
VL - 141
SP - 486
EP - 495
JO - Brain
JF - Brain
SN - 0006-8950
IS - 2
ER -