A Drosophila Model for LRRK2-Linked Parkinsonism
Mutations in the leucine-rich repeat kinase (LRRK2) gene cause late-onset autosomal dominant Parkinson's disease (PD) with pleiomorphic pathology. Previously, we and others found that expression of mutant LRRK2 causes neuronal degeneration in cell culture. Here we used the GAL4/UAS system to generate transgenic Drosophila expressing either wild-type human LRRK2 or LRRK2-G2019S, the most common mutation associated with PD. Expression of either wild-type human LRRK2 or LRRK2-G2019S in the photoreceptor cells caused retinal degeneration. Expression of LRRK2 or LRRK2-G2019S in neurons produced adult-onset selective loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Expression of mutant G2019S-LRRK2 caused a more severe parkinsonism-like phenotype than expression of equivalent levels of wild-type LRRK2. Treatment with L-DOPA improved mutant LRRK2-induced locomotor impairment but did not prevent the loss of tyrosine hydroxylase-positive neurons. To our knowledge, this is the first in vivo"gain-of-function" model which recapitulates several key features of LRRK2-linked human parkinsonism. These flies may provide a useful model for studying LRRK2-linked pathogenesis and for future therapeutic screens for PD intervention..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2008 |
|---|---|
| Erschienen: |
2008 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:105 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liu, Zhaohui [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Biological sciences |
|---|
| Förderinstitution / Projekttitel: |
|
|---|
| PPN (Katalog-ID): |
JST069534179 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | JST069534179 | ||
| 003 | DE-627 | ||
| 005 | 20240116234007.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 150325s2008 xx |||||o 00| ||eng c | ||
| 035 | |a (DE-627)JST069534179 | ||
| 035 | |a (JST)25451528 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liu, Zhaohui |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Drosophila Model for LRRK2-Linked Parkinsonism |
| 264 | 1 | |c 2008 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Mutations in the leucine-rich repeat kinase (LRRK2) gene cause late-onset autosomal dominant Parkinson's disease (PD) with pleiomorphic pathology. Previously, we and others found that expression of mutant LRRK2 causes neuronal degeneration in cell culture. Here we used the GAL4/UAS system to generate transgenic Drosophila expressing either wild-type human LRRK2 or LRRK2-G2019S, the most common mutation associated with PD. Expression of either wild-type human LRRK2 or LRRK2-G2019S in the photoreceptor cells caused retinal degeneration. Expression of LRRK2 or LRRK2-G2019S in neurons produced adult-onset selective loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Expression of mutant G2019S-LRRK2 caused a more severe parkinsonism-like phenotype than expression of equivalent levels of wild-type LRRK2. Treatment with L-DOPA improved mutant LRRK2-induced locomotor impairment but did not prevent the loss of tyrosine hydroxylase-positive neurons. To our knowledge, this is the first in vivo"gain-of-function" model which recapitulates several key features of LRRK2-linked human parkinsonism. These flies may provide a useful model for studying LRRK2-linked pathogenesis and for future therapeutic screens for PD intervention. | ||
| 540 | |a Copyright 2008 The National Academy of Sciences of the United States of America | ||
| 650 | 4 | |a Dopaminergic neuron | |
| 650 | 4 | |a Parkinson's disease | |
| 650 | 4 | |a Biological sciences |x Biology |x Cytology |x Cell biology |x Cells |x Neurons | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Population genetics |x Genetic variation |x Genetic mutation | |
| 650 | 4 | |a Biological sciences |x Biology |x Anatomy |x Nervous system |x Central nervous system |x Brain | |
| 650 | 4 | |a Biological sciences |x Biology |x Zoology |x Animals |x Invertebrates |x Arthropods |x Insects |x Flies |x Fruit flies |x Drosophila | |
| 650 | 4 | |a Health sciences |x Medical sciences |x Medical research |x Biomedical research |x Disease models | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Diseases |x Nervous system diseases |x Neurodegenerative diseases |x Parkinson disease | |
| 650 | 4 | |a Social sciences |x Population studies |x Mortality | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Phenotypes | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Genotypes | |
| 650 | 4 | |a Biological sciences |x Biology |x Zoology |x Animal anatomy |x Animal physiology |x Insect physiology |x Eclosion | |
| 650 | 4 | |a Biological sciences |x Biology |x Cytology |x Cell biology |x Cells |x Neurons | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Population genetics |x Genetic variation |x Genetic mutation | |
| 650 | 4 | |a Biological sciences |x Biology |x Anatomy |x Nervous system |x Central nervous system |x Brain | |
| 650 | 4 | |a Biological sciences |x Biology |x Zoology |x Animals |x Invertebrates |x Arthropods |x Insects |x Flies |x Fruit flies |x Drosophila | |
| 650 | 4 | |a Health sciences |x Medical sciences |x Medical research |x Biomedical research |x Disease models | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Diseases |x Nervous system diseases |x Neurodegenerative diseases |x Parkinson disease | |
| 650 | 4 | |a Social sciences |x Population studies |x Mortality | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Phenotypes | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Genotypes | |
| 650 | 4 | |a Biological sciences |x Biology |x Zoology |x Animal anatomy |x Animal physiology |x Insect physiology |x Eclosion | |
| 655 | 4 | |a research-article | |
| 700 | 1 | |a Wang, Xiaoyue |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xueping |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Haibing |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Qiuting |e verfasserin |4 aut | |
| 700 | 1 | |a Jiao, Yuchen |e verfasserin |4 aut | |
| 700 | 1 | |a Sawa, Akira |e verfasserin |4 aut | |
| 700 | 1 | |a Moran, Timothy |e verfasserin |4 aut | |
| 700 | 1 | |a Ross, Christopher A. |e verfasserin |4 aut | |
| 700 | 1 | |a Montell, Craig |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Wanli W. |e verfasserin |4 aut | |
| 773 | 1 | 8 | |g volume:105 |g year:2008 |g number:7 |g pages:2693-2698 |
| 856 | 4 | 0 | |u https://www.jstor.org/stable/25451528 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_JST | ||
| 951 | |a AR | ||
| 952 | |d 105 |j 2008 |e 7 |h 2693-2698 | ||