Coexistence of mutations in PINK1 and mitochondrial DNA in early onset Parkinsonism

Journal of Medical Genetics (Impact Factor: 6.34). 09/2008; 45(9):596-602. DOI: 10.1136/jmg.2008.058628
Source: PubMed


Various genes have been identified for monogenic disorders resembling Parkinson's disease. The products of some of these genes are associated with mitochondria and have been implicated in cellular protection against oxidative damage. In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism.
Patient's fibroblasts did not show variation in the mtDNA copy number or in the expression of the oxidative phosphorylation complexes. Sequence analysis of the patient's mtDNA presented two new missense mutations in the ND5 (m.12397A>G, p.T21A) and ND6 (m. 14319T>C, p.N119D) genes coding for two subunits of complex I. The two mutations were homoplasmic in both the patient and the patient's mother. Patient's fibroblasts resulted in enhanced constitutive production of the superoxide anion radical that was abrogated by inhibitor of the complex I. Moreover enzyme kinetic analysis of the NADH:ubiquinone oxidoreductase showed changes in the substrates affinity.
To our knowledge, this is the first report showing co-segregation of a Parkinson's disease related nuclear gene mutation with mtDNA mutation(s). Our observation might shed light on the clinical heterogeneity of the hereditary cases of Parkinson's disease, highlighting the hitherto unappreciated impact of coexisting mtDNA mutations in determining the development and the clinical course of the disease.

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    • "90% of PD cases are sporadic, 10% represent rare Mendelian hereditary forms, caused by a variety of autosomal mutations in more than 10 PARK genes [1] [2]. Mutations in mitochondrial DNA have also been found to contribute to PD development and clinical course [3]. Elucidation of the pathogenetic mechanism of familial cases, besides being strategic in designing predictive and therapeutic measures for these cases, can provide clues in identifying susceptible sites and networks, whose acquired alterations might be involved/responsible for development and progress in the life-course of sporadic PD. "
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    ABSTRACT: Parkinson's disease (PD) is the most common neurodegenerative movement disorder caused primarily by selective degeneration of the dopaminergic neurons in substantia nigra. In this work the proteomes extracted from primary fibroblasts of two unrelated, hereditary cases of PD patients, with different parkin mutations, were compared with the proteomes extracted from commercial adult normal human dermal fibroblasts (NHDF) and primary fibroblasts from the healthy mother of one of the two patients. The results show that the fibroblasts from the two different cases of parkin-mutant patients display analogous alterations in the expression level of proteins involved in different cellular functions, like cytoskeleton structure-dynamics, calcium homeostasis, oxidative stress response, proteins and RNA processing. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 06/2015; 1852(9). DOI:10.1016/j.bbadis.2015.06.015 · 4.66 Impact Factor
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    • "PD,earlyonset A12397G A>G T>A Piccolietal.[202] PD,earlyonset T14319C T>C N>D Piccolietal.[202] PD/MELAS 14787del4 TTAA-del I-frameshift deCooetal.[203] "
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    ABSTRACT: Mitochondria are essential for mammalian and human cell function as they generate ATP via aerobic respiration. The proteins required in the electron transport chain are mainly encoded by the circular mitochondrial genome but other essential mitochondrial proteins such as DNA repair genes, are coded in the nuclear genome and require transport into the mitochondria. In this review we summarize current knowledge on the association of point mutations and deletions in the mitochondrial genome that are detrimental to mitochondrial function and are associated with accelerated ageing and neurological disorders including Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis (ALS). Mutations in the nuclear encoded genes that disrupt mitochondrial functions are also discussed. It is evident that a greater understanding of the causes of mutations that adversely affect mitochondrial metabolism is required to develop preventive measures against accelerated ageing and neurological disorders caused by mitochondrial dysfunction.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 09/2013; 759C(1). DOI:10.1016/j.mrrev.2013.09.001 · 3.68 Impact Factor
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    • "Therefore, impairment of mitophagy due to PINK1 or Parkin mutations presumably leads to accumulation of dysfunctional mitochondria in the cell. This scenario may be an explanation for mitochondrial phenotypes, such as respiratory chain dysfunction [3], [4], [21] and elevated mitochondrial DNA mutational load [39], [40], [41] which have been observed in PINK1 or Parkin knockout models as well as PD patients with mutations in either gene (Figure 11). In accordance with our hypothesis, two studies in HeLa cells provided evidence that overexpression of Parkin leads to a significant loss of mitochondria [36], [37]. "
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    ABSTRACT: PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy. Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrial membrane potential (Δψ) inhibitors or H2O2 resulted in ubiquitination of Mfn1/2 but not of OPA1 or Fis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1 h of treatment. Upon combined inhibition of Δψ and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress. For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impair ubiquitination of Mitofusins. In the presence of UPS inhibitors, ubiquitinated Mitofusin is deubiquitinated by the UPS but not degraded, suggesting that the UPS is involved in Mitofusin degradation.
    PLoS ONE 03/2011; 6(3):e16746. DOI:10.1371/journal.pone.0016746 · 3.23 Impact Factor
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