Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa

University of Naples Federico II, Napoli, Campania, Italy
Brain (Impact Factor: 10.23). 03/2006; 129(Pt 3):686-94. DOI: 10.1093/brain/awl005
Source: PubMed

ABSTRACT Parkinson's disease is a frequent disorder caused primarily by the loss of dopaminergic neurons of the substantia nigra. Mutations in the PTEN-induced kinase (PINK1) gene, in addition to those in parkin and DJ-1, have been found in families with recessive early-onset Parkinson's disease. We screened for parkin and PINK1 mutations in a panel of 177 autosomal recessive Parkinson's disease families with ages at onset < or =60 years, mostly from Europe. In 7 unrelated families, we identified 10 pathogenic PINK1 mutations (5 missense, 2 nonsense and 3 frameshift deletion mutations), 8 of which were novel. All the mutations were in the homozygous or compound heterozygous states. Interestingly, pseudo-dominant inheritance was observed in a family with two different mutations. The clinical characteristics of 12 PINK1 patients and 114 parkin patients were similar, even for signs such as dystonia at onset and increased reflexes, which were thought to be specific to parkin. In contrast, onset in patients with PINK1 mutations was earlier and increased reflexes were found more frequently than in patients without PINK1 or parkin mutations. These results suggest that PINK1 is the second most frequent causative gene in early-onset Parkinson's disease with a slowly progressive phenotype, indistinguishable from early-onset patients with parkin mutations.

  • Source
    • "PINK1 is a mitochondrial-targeted kinase (Clark et al., 2006; Gandhi et al., 2006; Valente et al., 2004), whilst Parkin is an E3 ubiquitin ligase which seems to be specifically recruited to mitochondria upon PINK1 activation (Clark et al., 2006; Pallanck and Greenamyre, 2006). Several PINK1 (PTEN-induced putative kinase 1) and Parkin mutations have been detected in sporadic cases of Parkinson's disease patients (Ibanez et al., 2006). In flies, PINK1 mutants have reduced ATP levels, they are sensitive to multiple stresses, and have an overall shorter lifespan than wild-type controls (Clark et al., 2006), indicating the significance of mitochondrial quality control in ageing. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ageing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, we consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.
    Ageing research reviews 05/2012; 12(1). DOI:10.1016/j.arr.2012.05.001 · 7.63 Impact Factor
  • Source
    • "Missense or truncating mutations of PINK1 gene cause recessive familial type 6 of Parkinson's disease (PARK6) [2] [3] [4] [5] [6]. PINK1 is believed to function as a mitochondrial Ser/Thr protein kinase and protect SN dopaminergic neurons against various cellular stresses [2] [7] [13] [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in PTEN-induced kinase 1 (PINK1) gene cause recessive familial type 6 of Parkinson's disease (PARK6). PINK1 is believed to exert neuroprotective effect on SN dopaminergic cells by acting as a mitochondrial Ser/Thr protein kinase. Autosomal recessive inheritance indicates the involvement of loss of PINK1 function in PARK6 pathogenesis. In the present study, confocal imaging of cultured SN dopaminergic neurons prepared from PINK1 knockout mice was performed to investigate physiological importance of PINK1 in maintaining mitochondrial membrane potential (ΔΨ(m)) and mitochondrial morphology and test the hypothesis that PARK6 mutations cause the loss of PINK1 function. PINK1-deficient SN dopaminergic neurons exhibited a depolarized ΔΨ(m). In contrast to long thread-like mitochondria of wild-type neurons, fragmented mitochondria were observed from PINK1-null SN dopaminergic cells. Basal level of mitochondrial superoxide and oxidative stressor H(2)O(2)-induced ROS generation were significantly increased in PINK1-deficient dopaminergic neurons. Overexpression of wild-type PINK1 restored hyperpolarized ΔΨ(m) and thread-like mitochondrial morphology and inhibited ROS formation in PINK1-null dopaminergic cells. PARK6 mutant (G309D), (E417G) or (CΔ145) PINK1 failed to rescue mitochondrial dysfunction and inhibit oxidative stress in PINK1-deficient dopaminergic neurons. Mitochondrial toxin rotenone-induced cell death of dopaminergic neurons was augmented in PINK1-null SN neuronal culture. These results indicate that PINK1 is required for maintaining normal ΔΨ(m) and mitochondrial morphology of cultured SN dopaminergic neurons and exerts its neuroprotective effect by inhibiting ROS formation. Our study also provides the evidence that PARK6 mutant (G309D), (E417G) or (CΔ145) PINK1 is defective in regulating mitochondrial functions and attenuating ROS production of SN dopaminergic cells.
    Biochimica et Biophysica Acta 03/2011; 1812(6):674-84. DOI:10.1016/j.bbadis.2011.03.007 · 4.66 Impact Factor
  • Source
    • "Point mutations in the PTEN-induced kinase or PINK1 gene, a putative mitochondrial kinase at the PARK6 locus, are the second most frequently occurring cause of autosomal recessively inherited early-onset PD (Valente et al. 2001,2004; Hatano et al. 2004; Rogaeva et al. 2004; Rohe et al. 2004; Bonifati et al. 2005; Bender et al. 2006; Ibanez et al. 2006). PINK1 is present throughout the brain and localizes to mitochondria where it is thought to protect against mitochondrial dysfunction (Gandhi et al. 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The identification of genes linked to neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Parkinson's disease (PD) has led to the development of animal models for studying mechanism and evaluating potential therapies. None of the transgenic models developed based on disease-associated genes have been able to fully recapitulate the behavioral and pathological features of the corresponding disease. However, there has been enormous progress made in identifying potential therapeutic targets and understanding some of the common mechanisms of neurodegeneration. In this review, we will discuss transgenic animal models for AD, ALS, HD and PD that are based on human genetic studies. All of the diseases discussed have active or complete clinical trials for experimental treatments that benefited from transgenic models of the disease.
    Journal of Neural Transmission 10/2010; 118(1):27-45. DOI:10.1007/s00702-010-0476-6 · 2.87 Impact Factor
Show more