PINK1 (PARK6) associated Parkinson disease in Ireland

Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK.
Neurology (Impact Factor: 8.29). 11/2004; 63(8):1486-8. DOI: 10.1212/01.WNL.0000142089.38301.8E
Source: PubMed


Mutations in the PINK1 gene have recently been shown to cause autosomal recessive Parkinson disease (PD). The authors assessed the prevalence of PINK1 gene mutations in 290 well-characterized early- and late-onset PD patients from Ireland. In a 51-year-old PD patient with a family history of PD, the authors identified a novel heterozygous mutation (R147H) in exon 2 of the PINK1 gene. Overall, these data indicate that PINK1 mutations are a rare cause of PD in Ireland.

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Available from: Owen A Ross, Jan 17, 2014
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    • "PINK1 is a gene that also causes early cases of PD, and was first identified in an Italian family on the chromosome 1p35-p36 [16]. PINK1 stands for (PTEN)-induced putative kinase 1 and has functions that aid the mitochondria, such as protecting it from damage [17]. "
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    ABSTRACT: Background Parkinson’s disease (PD) continues to be an important neurological disorder. It is caused by the loss of dopaminergic neurons in the substantia nigra. Dopamine, the neurotransmitter produced from dopaminergic neurons, is a major precursor of endogenous morphine. There are approximately 18 genes associated with PD; their roles have not yet been completely established. PARK2 is a gene that encodes for the protein parkin, and PINK1 is a gene that encodes for PTEN-induced putative kinase 1. Material/Methods Our objective was to determine if morphine treatment of HTB-11 cells affects the expression of PINK1 and PARK2. HTB-11 cells were treated with 10−7 M morphine for 2 h and a microarray analysis was conducted. To verify the microarray analysis, 3 Q-PCR trials were run using 10−6 M naloxone, morphine (10−7 M), or a naloxone/morphine mix. Results In both the microarray analysis and the Q-PCR analysis, PARK2 was up-regulated and PINK1 was down-regulated. Conclusions Morphine can affect the expression of PD-associated genes.
    05/2014; 20:63-9. DOI:10.12659/MSMBR.890557
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    • "Consistent with this hypothesis, a truncated fragment of the PINK1 protein containing the active kinase domain was shown to be sufficient to provide cells with protection against MPTP toxicity, but this effect was abrogated by the presence of kinase-inactivating mutations (4). However, a series of PD-associated mutations lie within the N-terminal region of the PINK1 protein and it is mechanistically unclear how these mutations would account for loss of kinase function (5–7). "
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    ABSTRACT: Mutations in PTEN-induced kinase 1 (PINK1) cause early onset autosomal recessive Parkinson's disease (PD). PINK1 is a 63 kDa protein kinase, which exerts a neuroprotective function and is known to localize to mitochondria. Upon entry into the organelle, PINK1 is cleaved to produce a ∼53 kDa protein (ΔN-PINK1). In this paper, we show that PINK1 is cleaved between amino acids Ala-103 and Phe-104 to generate ΔN-PINK1. We demonstrate that a reduced ability to cleave PINK1, and the consequent accumulation of full-length protein, results in mitochondrial abnormalities reminiscent of those observed in PINK1 knockout cells, including disruption of the mitochondrial network and a reduction in mitochondrial mass. Notably, we assessed three N-terminal PD-associated PINK1 mutations located close to the cleavage site and, while these do not prevent PINK1 cleavage, they alter the ratio of full-length to ΔN-PINK1 protein in cells, resulting in an altered mitochondrial phenotype. Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and that loss of PARL results in aberrant PINK1 cleavage in mammalian cells. These combined results suggest that PINK1 cleavage is important for basal mitochondrial health and that PARL cleaves PINK1 to produce the ΔN-PINK1 fragment.
    Human Molecular Genetics 03/2011; 20(5):867-79. DOI:10.1093/hmg/ddq526 · 6.39 Impact Factor
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    • "The first reported PINK1 mutations, G309D and the truncation mutant W437X, were identified in patients of Spanish and Italian origin, respectively (Valente et al., 2004a). Over 20 pathological mutations have now been identified in PINK1 varying from point mutations, truncations and whole gene heterozygous deletions (Klein et al., 2006, Marongiu et al., 2007, Zadikoff et al., 2006), which between them account for between 1–9% of cases with early onset parkinsonism (Healy et al., 2004, Li et al., 2005, Rohe et al., 2004, Tan et al., 2006, Tan et al., 2005, Valente et al., 2004b). "
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    ABSTRACT: Mutations in parkin, PTEN-induced kinase 1 (PINK1) and DJ-1 can all cause autosomal recessive forms of Parkinson's disease. Recent data suggest that these recessive parkinsonism-associated genes converge within a single pathogenic pathway whose dysfunction leads to the loss of substantia nigra pars compacta neurons. The major common functional effects of all three genes relate to mitochondrial and oxidative damage, with a possible additional involvement of the ubiquitin proteasome system. This review highlights the role of the mitochondrial kinase, PINK1, in protection against mitochondrial dysfunction and how this might relate to loss of substantia nigra neurons in recessive parkinsonism.
    The international journal of biochemistry & cell biology 11/2009; 41(10):2025-35. DOI:10.1016/j.biocel.2009.02.018 · 4.05 Impact Factor
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