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Doktorsavhandling vid Karolinska Institutet |
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Sandebring, AnnaMechanism of action of autosomal recessive juvenile parkinsonism gene mutationsFredagen den 19 februari 2010, kl. 09.30. Hörsalen, Novum Plan 4, Huddinge. |
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| ISBN: 978-91-7409-803-7 | Diss: 10:39 |
Abstract:
Parkinson Disease (PD) is the most common neurodegenerative movement disorder. Although PD is a largely sporadic disease, several genes has been linked to familial forms of PD. This thesis focuses on the mechanism of function of the Autosomal Recessively Juvenile Parkinsonism (AR-JP) associated genes parkin, PTEN induced kinase 1 (PINK1) and DJ-1.
In Paper I we described a novel interaction between the E3 ubiquitin ligase parkin and phospholipase C-gamma1 (PLCgamma1). We further demonstrated that parkin ubiquitinates and regulates PLCgamma1 levels.
Impairment in calcium homeostasis has been suggested to be associated to PD related cell death. Since PLCgamma1 is an important enzyme for regulating calcium, we continued by studying the downstream consequences of parkin impairment in the context of PLCgamma1-mediated signaling. This study resulted in Paper II where we established that parkin deficiency leads to increased lipid hydrolysis and cytosolic calcium levels due to altered PLCgamma1 activity. When we blocked calcium release from intracellular stores in parkin-mutant cells, the viability after exposure to oxidative stress was increased.
Previous studies suggest that mitochondrial dysfunction is related to neurodegeneration in PD. In Paper III and IV, we elucidated the roles of DJ-1 and PINK1 in mitochondrial morphology and dynamics. We showed that DJ-1 or PINK1 knock-down (KD) increased mitochondrial fragmentation and that blocking fission could reverse these phenotypes. In DJ-1 KD, we found that fission was related to oxidative stress, whereas in PINK1-deficient cells the mitochondrial abnormality was likely a consequence of a loss of mitochondrial membrane potential and increased calcineurin activity. In Paper V we analyzed mitochondrial motility in differentiated cells. By live imaging we demonstrated that KD of either DJ-1 or PINK1 decreased the rate of mitochondrial motility in neurites. Blocking fission eliminated the difference between the control cells and parkinsonism associated KD cells, suggesting that balanced mitochondrial dynamics is important for neuritic motility.
In conclusion, PD is a multi-factorial disorder involving several degenerative processes and signaling pathways. The AR-JP studies presented in this thesis may help to bring light to the understanding of the underlying mechanisms of PD and to develop novel treatment strategies.
List of papers
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Parkin-mediated Ubiquitination Regulates Phospholipase C-gamma1. Dehvari N, Sandebring A, Flores-Morales A, Mateos L, Chuan YC, Goldberg MS, Cookson MR, Cowburn RF, Cedazo-Mínguez A J Cell Mol Med, 2008; Jul 30: Epub ahead of print |
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Parkin deficiency disrupts calcium homeostasis by modulating phospholipase C signalling. Sandebring A, Dehvari N, Perez-Manso M, Thomas KJ, Karpilovski E, Cookson MR, Cowburn RF, Cedazo-Mínguez A FEBS J, 2009; 276(18): 5041-52. Epub 2009 Aug 3 |
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Increased oxidative stress in DJ-1-deficient cells is associated with multiple mitochondrial abnormalities. Blackinton J, Thomas KJ, Mc Coy M, Beilina A, van der Brug M, Sandebring A, Miller D, Cedazo-Minguez A, Cookson MR Manuscript |
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Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. Sandebring A, Thomas KJ, Beilina A, van der Brug M, Cleland MM, Ahmad R, Miller DW, Zambrano I, Cowburn RF, Behbahani H, Cedazo-Mínguez A, Cookson MR PLoS One, 2009; 4(5): e5701 |
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PINK1 or DJ-1 deficiencies impair neuritic motility of mitochondria. Sandebring A, Perez-Manso M, Cookson MR, Cedazo-Minguez A Manuscript |
