Dataset Information

Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.

ABSTRACT:

Background

Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.

Methodology/principal findings

Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.

Conclusion

Thus, aging Pink1(-/-) mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.

SUBMITTER: Gispert S

PROVIDER: S-EPMC2686165 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Publications

Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.

Gispert Suzana S Ricciardi Filomena F Kurz Alexander A Azizov Mekhman M Hoepken Hans-Hermann HH Becker Dorothea D Voos Wolfgang W Leuner Kristina K Müller Walter E WE Kudin Alexei P AP Kunz Wolfram S WS Zimmermann Annabelle A Roeper Jochen J Wenzel Dirk D Jendrach Marina M García-Arencíbia Moisés M Fernández-Ruiz Javier J Huber Leslie L Rohrer Hermann H Barrera Miguel M Reichert Andreas S AS Rüb Udo U Chen Amy A Nussbaum Robert L RL Auburger Georg G

PloS one 20090603 6

<h4>Background</h4>Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.<h4>Methodology/principal findings</h4>Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements oc ...[more]

PMID: 19492057

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Project description:Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2-3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient's derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.

Dataset Information

Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.

Background

Methodology/principal findings

Conclusion

Publications

Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.

Similar Datasets

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