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Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice
- Source :
- Proceedings of the National Academy of Sciences. 115:1635-1640
- Publication Year :
- 2018
- Publisher :
- Proceedings of the National Academy of Sciences, 2018.
-
Abstract
- Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson's disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons. Accompanying the loss of DA neurons are DA-dependent behavioral deficits and α-synuclein pathology that are also LRRK2 GS kinase-dependent. Transmission EM reveals that that there is an LRRK2 GS kinase-dependent significant reduction in synaptic vesicle number and a greater abundance of clathrin-coated vesicles in DA neurons. These transgenic mice indicate that LRRK2-induced DA and NE neurodegeneration is kinase-dependent and can occur in a cell-autonomous manner. Moreover, these mice provide a substantial advance in animal model development for LRRK2-associated PD and an important platform to investigate molecular mechanisms for how DA neurons degenerate as a result of expression of mutant LRRK2.
- Subjects :
- Male
0301 basic medicine
Genetically modified mouse
medicine.medical_specialty
Dopamine
Transgene
Mice, Transgenic
Motor Activity
Biology
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mice
Norepinephrine
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Animals
Humans
Multidisciplinary
Behavior, Animal
Tyrosine hydroxylase
Dopaminergic Neurons
Dopaminergic
Neurodegeneration
Age Factors
Neurodegenerative Diseases
Biological Sciences
medicine.disease
LRRK2
nervous system diseases
Disease Models, Animal
030104 developmental biology
Endocrinology
Mutation
alpha-Synuclein
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 115
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....96c8a0b16ea773f7ed97d85bcc341dd6