Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

By E. Valente, P. Abou-Sleiman, V. Caputo, M. Muqit, K. Harvey, S. Gispert, Zeeshan Ali, D. Del Turco, A. Bentivoglio, D. Healy and 12 more. Science, 2004

3,625 citations recorded by the source corpus.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/2ac6a0a7177770012ba45122bf8947c6325cc261

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In Molecular Biology

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In Neurology

1. R. Youle
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4. T. Dawson
5. S. Jin
6. Derek P. Narendra
7. P. Jenner
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Citations in the corpus

• PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy (2010, background): “In addition, PINK1 (PTEN-induced putative kinase 1) was identified in 2004 as the gene responsible for another form of earlyonset PD (Valente et al., 2004).”
• The Fly as a Model for Neurodegenerative Diseases: Is It Worth the Jump? (2007, positive): “seemed to have alleviated this problem. Specifically, the authors inactivated DJ-1 α by transgenic RNAi to reveal that DJ-1 α knockdown flies show cellular accumulation of reactive oxygen species, hypersensitivity to oxidative stress, and degeneration of dopaminergic and photoreceptor neurons. Fur”
• Epidemiology and etiology of Parkinson’s disease: a review of the evidence (2011, background): “Two homozygous point mutations in the PINK1 (PTEN-induced putative kinase 1) gene were reported in two Italian and one Spanish family with autosomal recessive parkinsonism [183].”
• The genetic epidemiology of neurodegenerative disease. (2005, background): “34]; PTEN-induced putative kinase I [PINK1 or PARK6; ref.”
• Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress (2008, neutral): “Bioinformatics analysis reveals that PINK1 is a putative serine-threonine kinase with a mitochondrial targeting motif at its N-terminal end (9).”
• PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death (2009, background): “A number of these genes, namely PINK1, DJ-I, and Omi/HtrA2, encode mitochondrially located proteins, further implicating mitochondrial dysfunction as the primary event sufficient to cause PD. Mutations in the PINK1 gene cause autosomal recessive PD (Valente et al., 2004).”
• Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL (2010, background): “ized to mitochondria (Valente et al., 2004), whereas Parkin is”
• Genetic Animal Models of Parkinson’s Disease (2010, positive): “PD due to PINK1 mutations is inherited in a recessive fashion, and mutations are thought to lead to a loss of function (Valente et al., 2004).”
• Genetics of Parkinson's disease. (2012, background): “The frequency of PINK1 mutations is in the range of 1%–9%, with considerable variation across different ethnic groups (Healy et al. 2004; Rogaeva et al. 2004; Valente et al. 2004; Bonifati et al. 2005; Klein et al. 2005; Li et al. 2005).”
• Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease. (2007, background): “Pink1 bears an N-terminal mitochondrial targeting sequence (MTS) and colocalizes predominantly with mitochondrial markers in cultured mammalian cells [19 ,30] and in vivo [18 ].”
• Atg8 family LC3/GABARAP proteins are crucial for autophagosome–lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation (2016, background): “, 2001) and the role of PINK1 and Parkin in Parkinson’s disease (Kitada et al., 1998; Valente et al., 2004).”
• PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 (2012, background): “The human PINK1 gene encodes a 581 residue serine– threonine kinase unique among all protein kinases since it contains an N-terminal mitochondrial targeting motif (residues 1–34) [1,2].”