Parkin Loss Leads to PARIS-dependent Declines in Mitochondrial Mass and Respiration

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Sep 2

PMID 26324925

Citations 129

Authors

Daniel A Stevens

Yunjong Lee

Ho Chul Kang

Byoung Dae Lee

Yun-Il Lee

Aaron Bower

Haisong Jiang

Sung-Ung Kang

Shaida A Andrabi

Valina L Dawson

Joo-Ho Shin

Ted M Dawson

Affiliations

Soon will be listed here.

Abstract

Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.

Citing Articles

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References

Palikaras K, Lionaki E, Tavernarakis N . Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature. 2015; 521(7553):525-8. DOI: 10.1038/nature14300. View

Dawson T, Dawson V . Parkin plays a role in sporadic Parkinson's disease. Neurodegener Dis. 2013; 13(2-3):69-71. PMC: 3984465. DOI: 10.1159/000354307. View

Cookson M . Parkin's substrates and the pathways leading to neuronal damage. Neuromolecular Med. 2003; 3(1):1-13. DOI: 10.1385/NMM:3:1:1. View

Yao D, Gu Z, Nakamura T, Shi Z, Ma Y, Gaston B . Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A. 2004; 101(29):10810-4. PMC: 490016. DOI: 10.1073/pnas.0404161101. View

St-Pierre J, Drori S, Uldry M, Silvaggi J, Rhee J, Jager S . Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006; 127(2):397-408. DOI: 10.1016/j.cell.2006.09.024. View

Kageyama Y, Zhang Z, Roda R, Fukaya M, Wakabayashi J, Wakabayashi N . Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage. J Cell Biol. 2012; 197(4):535-51. PMC: 3352955. DOI: 10.1083/jcb.201110034. View

Lin J, Handschin C, Spiegelman B . Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005; 1(6):361-70. DOI: 10.1016/j.cmet.2005.05.004. View

Kim M, Mauro S, Gevry N, Lis J, Kraus W . NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1. Cell. 2004; 119(6):803-14. DOI: 10.1016/j.cell.2004.11.002. View

Shin J, Ko H, Kang H, Lee Y, Lee Y, Pletinkova O . PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Cell. 2011; 144(5):689-702. PMC: 3063894. DOI: 10.1016/j.cell.2011.02.010. View

10.

Corti O, Lesage S, Brice A . What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol Rev. 2011; 91(4):1161-218. DOI: 10.1152/physrev.00022.2010. View

11.

Dawson T, Ko H, Dawson V . Genetic animal models of Parkinson's disease. Neuron. 2010; 66(5):646-61. PMC: 2917798. DOI: 10.1016/j.neuron.2010.04.034. View

12.

McCaffery J, Farquhar M . Localization of GTPases by indirect immunofluorescence and immunoelectron microscopy. Methods Enzymol. 1995; 257:259-79. DOI: 10.1016/s0076-6879(95)57031-4. View

13.

Myeku N, Figueiredo-Pereira M . Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1/p62. J Biol Chem. 2011; 286(25):22426-40. PMC: 3121389. DOI: 10.1074/jbc.M110.149252. View

14.

Moore D . Parkin: a multifaceted ubiquitin ligase. Biochem Soc Trans. 2006; 34(Pt 5):749-53. DOI: 10.1042/BST0340749. View

15.

Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S . Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998; 392(6676):605-8. DOI: 10.1038/33416. View

16.

Meng F, Yao D, Shi Y, Kabakoff J, Wu W, Reicher J . Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation. Mol Neurodegener. 2011; 6:34. PMC: 3120712. DOI: 10.1186/1750-1326-6-34. View

17.

Geisler S, Holmstrom K, Skujat D, Fiesel F, Rothfuss O, Kahle P . PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010; 12(2):119-31. DOI: 10.1038/ncb2012. View

18.

Shaltouki A, Sivapatham R, Pei Y, Gerencser A, Momcilovic O, Rao M . Mitochondrial alterations by PARKIN in dopaminergic neurons using PARK2 patient-specific and PARK2 knockout isogenic iPSC lines. Stem Cell Reports. 2015; 4(5):847-59. PMC: 4437475. DOI: 10.1016/j.stemcr.2015.02.019. View

19.

LaVoie M, Ostaszewski B, Weihofen A, Schlossmacher M, Selkoe D . Dopamine covalently modifies and functionally inactivates parkin. Nat Med. 2005; 11(11):1214-21. DOI: 10.1038/nm1314. View

20.

Wang C, Ko H, Thomas B, Tsang F, Chew K, Tay S . Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function. Hum Mol Genet. 2005; 14(24):3885-97. DOI: 10.1093/hmg/ddi413. View