Unknown

Dataset Information

0

Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress.


ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. PARK2 mutations cause early-onset forms of PD. PARK2 encodes an E3 ubiquitin ligase, Parkin, that can selectively translocate to dysfunctional mitochondria to promote their removal by autophagy. However, Parkin knockout (KO) mice do not display signs of neurodegeneration. To assess Parkin function in vivo, we utilized a mouse model that accumulates dysfunctional mitochondria caused by an accelerated generation of mtDNA mutations (Mutator mice). In the absence of Parkin, dopaminergic neurons in Mutator mice degenerated causing an L-DOPA reversible motor deficit. Other neuronal populations were unaffected. Phosphorylated ubiquitin was increased in the brains of Mutator mice, indicating PINK1-Parkin activation. Parkin loss caused mitochondrial dysfunction and affected the pathogenicity but not the levels of mtDNA somatic mutations. A systemic loss of Parkin synergizes with mitochondrial dysfunction causing dopaminergic neuron death modeling PD pathogenic processes.

SUBMITTER: Pickrell AM 

PROVIDER: S-EPMC4803114 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications

Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress.

Pickrell Alicia M AM   Huang Chiu-Hui CH   Kennedy Scott R SR   Ordureau Alban A   Sideris Dionisia P DP   Hoekstra Jake G JG   Harper J Wade JW   Youle Richard J RJ  

Neuron 20150701 2


Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. PARK2 mutations cause early-onset forms of PD. PARK2 encodes an E3 ubiquitin ligase, Parkin, that can selectively translocate to dysfunctional mitochondria to promote their removal by autophagy. However, Parkin knockout (KO) mice do not display signs of neurodegeneration. To assess Parkin function in vivo, we utilized a mouse model that accumulates dysfunctional mitochondri  ...[more]

Similar Datasets

| S-EPMC2775382 | biostudies-other
| S-EPMC2784968 | biostudies-literature
2022-07-31 | GSE206366 | GEO
| S-EPMC3387060 | biostudies-literature
| S-EPMC5643088 | biostudies-literature
| S-EPMC3058355 | biostudies-literature
| S-EPMC3140825 | biostudies-other
| S-EPMC9758156 | biostudies-literature
| S-EPMC153078 | biostudies-literature
| S-EPMC4448554 | biostudies-literature