Analysis of the PINK1 Gene in a Large Cohort of Cases With Parkinson Disease

Rogaeva, Ekaterina; Johnson, Janel O.; Lang, Anthony E.; Gulick, Cindy; Gwinn‐Hardy, Katrina; Kawarai, Toshitaka; Sato, Christine; Morgan, Angharad R.; Werner, John S.; Nussbaum, Robert L.; Petit, Agnès; Okun, Michael S.; McInerney, A.; Mandel, Ronald J.; Groen, Justus L.; Fernández, Hubert H.; Postuma, Ron; Foote, Kelly D.; Salehi-Rad, Shabnam; Liang, Yan; Reimsnider, Sharon; Tandon, Anurag; Hardy, John; George-Hyslop, Peter St; Singleton, Andrew B.

doi:10.1001/archneur.61.12.1898

Cited by 169 publications

(139 citation statements)

References 17 publications

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“…Finally, we obtained primary cultures of human skin fibroblasts from a neurologically normal elderly male and from a 74-year-old male familial PD patient with the compound E204K/L489P mutation in PINK1 (2). Reverse transcription PCR studies confirmed that PINK1 mRNA is robustly expressed in the fibroblasts of both the normal control and the PINK1 mutant carrier.…”

Section: Resultsmentioning

confidence: 95%

“…We have recently identified the first reported compound heterozygous mutation (E240K and L489P) in a family with early onset Parkinson disease (2). We therefore created PINK1 cDNA constructs containing the following: 1) a human wild-type PINK1; 2) the PD-related E240K PINK1 mutant; 3) the PD-related L489P PINK1 mutant; 4) a double mutation (E240K/L489P); and 5) an artificial kinase dead mutant (K219M) that eliminated the Lys-219 residue that is predicted to be critical for the putative kinase activity of PINK1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Human Skin Fibroblasts Primary Cultures-With informed consent, forearm skin biopsies were performed on both a 74-year-old male Parkinson disease patient with a pathogenic compound heterozygous E240K/L489P mutation in the PINK1 gene and a 76-year-old neurological normal male (2). ϳ300 mg of tissue were immediately placed in 10 ml of transport media (␣-minimal essential medium supplemented with 20% fetal calf serum (Wisent) and 1% penicillin and streptomycin).…”

Section: Methodsmentioning

confidence: 99%

“…Mutations in the ␣-synuclein (5), LRRK2 (leucine-rich repeat kinase 2) and UCH-L1 (ubiquitin C-terminal esterase L1) genes cause dominant forms of familial PD. In contrast, mutations in parkin (6), DJ-1 (7,8), and the newly identified PTEN (phosphatase and tensin homologue on chromosome 10)-induced kinase 1 (PINK1) (1,2) are responsible for recessive forms of familial PD.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

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Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Petit

Kawarai²,

Paitel³

et al. 2005

Journal of Biological Chemistry

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294

239

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Mutations in the PTEN-induced kinase 1 (PINK1) gene have recently been implicated in autosomal recessive early onset Parkinson Disease (1, 2). To investigate the role of PINK1 in neurodegeneration, we designed human and murine neuronal cell lines expressing either wild-type PINK1 or PINK1 bearing a mutation associated with Parkinson Disease. We show that under basal and staurosporine-induced conditions, the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells was lower in wild-type PINK1 expressing SH-SY5Y cells than in mock-transfected cells. This phenotype was due to a PINK1-mediated reduction in cytochrome c release from mitochondria, which prevents subsequent caspase-3 activation. We show that overexpression of wild-type PINK1 strongly reduced both basal and staurosporine-induced caspase 3 activity. Overexpression of wild-type PINK1 also reduced the levels of cleaved caspase-9, caspase-3, caspase-7, and activated poly(ADP-ribose) polymerase under both basal and staurosporine-induced conditions. In contrast, Parkinson disease-related mutations and a kinase-inactive mutation in PINK1 abrogated the protective effect of PINK1. Together, these results suggest that PINK1 reduces the basal neuronal pro-apoptotic activity and protects neurons from staurosporine-induced apoptosis. Loss of this protective function may therefore underlie the degeneration of nigral dopaminergic neurons in patients with PINK1 mutations. Parkinson disease (PD)2 is the most common neurodegenerative movement disorder, affecting ϳ1% of the population by age 65 years (3, 4). It is characterized by the predominant degeneration of midbrain dopaminergic neurons. Although most patients with PD are sporadic, familial cases represent ϳ10% of all diagnoses. To date, six genes responsible for inherited forms of PD have been identified. Mutations in the ␣-synuclein (5), LRRK2 (leucine-rich repeat kinase 2) and UCH-L1 (ubiquitin C-terminal esterase L1) genes cause dominant forms of familial PD. In contrast, mutations in parkin (6), DJ-1 (7,8), and the newly identified PTEN (phosphatase and tensin homologue on chromosome 10)-induced kinase 1 (PINK1) (1, 2) are responsible for recessive forms of familial PD.PINK1 encodes a highly conserved, 581-amino acid, putative serinethreonine protein kinase and is a member of a small family of novel kinases including CLIK1 (CLP-36 interacting kinase)/PDLIM1 kinases. Bioinformatic analysis suggests that residues Gly-193 to Leu-507 comprise the catalytic domain, residues Gly-193 to Lys-219 form the ATPbinding cassette (with Tyr-166 as an autophosphorylated regulatory residue), and residues Asp-384 to Glu-417 form an activation loop (Fig. 1). PINK1 is transcriptionally transactivated by the PTEN gene (9) and is expressed at variable levels in different cancer cell types. Valente et al. showed that overexpressed, epitope-tagged PINK1 localized to mitochondria and may have a protective function against cell death (1).To further investigate the role of PINK1 in neuronal ap...

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

See 2 more Smart Citations

Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Petit

Kawarai²,

Paitel³

et al. 2005

Journal of Biological Chemistry

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294

239

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“…Other studies that screened PD patients (most often with early onset) from different populations reported PINK mutations in 0.5 to 9% of cases [232][233][234][235][236]. Thus, PINK1 mutations seem to be more rare compared to Parkin mutations.…”

Section: Pink1 (Park6)mentioning

confidence: 97%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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T313M PINK1 Mutation in an Extended Highly Consanguineous Saudi Family With Early-Onset Parkinson Disease

Chishti¹,

Bohlega²,

Ahmed³

et al. 2006

Arch Neurol

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Background: To date, 5 well-confirmed genes for Parkinson disease (PD) have been identified, including 3 autosomal recessive genes: PTEN-induced putative kinase 1 (PINK1), parkin, and DJ-1. Almost nothing is known about the genetics of PD in Saudi Arabia; however, consanguineous families, not infrequent in this population, could be important in the evaluation of known PD genes and the search for new PD factors in the future.Objective: To investigate known recessive PD genes in 5 consanguineous Saudi families with PD. Design:The entire open frame as well as the untranslated region and all 5Ј and 3Ј intron-exon boundaries of the PINK1, parkin, and DJ-1 genes were sequenced in 5 probands in Saudi families.Results: Four of 5 probands tested negative for PINK1, parkin, and DJ-1 mutations. However, in a large Saudi family with PD with at least 3 consanguineous marriages between first cousins, we detected a threonine to

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Analysis of the PINK1 Gene in a Large Cohort of Cases With Parkinson Disease

Abstract: Autosomal recessive mutations in PINK1 are a rare cause of young-onset Parkinson disease.

Cited by 169 publications

References 17 publications

Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

T313M PINK1 Mutation in an Extended Highly Consanguineous Saudi Family With Early-Onset Parkinson Disease

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