Early-onset parkinsonism associated with
            <i>PINK1</i>
            mutations

Bonifati, Vincenzo; Rohé, Christan F.; Breedveld, Guido J.; Fabrizio, Edito; Mari, Michele; Tassorelli, C.; Tavella, Alessia; Marconi, Roberto; Nicholl, David; Chien, Hsin Fen; Fincati, E.; Abbruzzese, Giovanni; Marini, P.; Gaetano, Antonio De; Horstink, M.W.I.M.; Maat-Kievit, J.A.; Sampaio, Cristina; Antonini, Angelo; Stocchi, Fabrizio; Montagna, Pasquale; Toni, Vincenzo; Guidi, Marco; Libera, A. Dalla; Tinazzi, Michèle; Pandis, Francesca De; Fabbrini, Giovanni; Goldwurm, Stefano; Klein, Annelies de; Barbosa, Egberto Reis; Lopiano, Leonardo; Martignoni, E.; Lamberti, Paolo; Vanacore, Nicola; Meco, Giuseppe; Oostra, Ben A.

doi:10.1212/01.wnl.0000167546.39375.82

Cited by 316 publications

(234 citation statements)

References 25 publications

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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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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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“…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).…”

Section: Pink1 (Park6)mentioning

confidence: 99%

Genetics of Parkinson's Disease

Klein

Westenberger

2012

Cold Spring Harbor Perspectives in Medicine

1,044

726

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Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

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“…The deduced amino acid sequence indicates that PINK1 contains a mitochondrial targeting motif (amino acids 1-34) and a kinase domain (amino acids 156-509) that is highly homologous to Ca 2ϩ /calmodulin-dependent kinases. Since the first report linking recessively inherited nonsense (W437X) and missense (G309D) mutations in PINK1 to familial PARK6 cases (3), large numbers (Ͼ30) of additional truncation and missense mutations have been identified in early-onset PD cases with or without family history (5)(6)(7)(8)(9)(10)(11). Genetic analysis revealed that homozygous and compound heterozygous mutations in PINK1 are highly penetrant and are rather common among early-onset (Ͻ50) PD patients and that heterozygous mutations are present among late-onset PD cases at reduced penetrance (6,7,10).…”

mentioning

confidence: 99%

Impaired dopamine release and synaptic plasticity in the striatum of PINK1 -deficient mice

Pisani

Porter

Yamaguchi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

470

441

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Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-offunction mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1 ؊/؊ mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1 ؊/؊ mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1 ؊/؊ mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or L-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.neurodegeneration ͉ Parkinson's disease ͉ substantia nigra P arkinson's disease (PD) is the most common movement disorder and is characterized by bradykinesia, rigidity, resting tremor, and postural instability. These clinical features are thought to result from reduced dopaminergic input to the striatum and the loss of dopaminergic neurons in the pars compacta of the substantia nigra (SNpc). Although the occurrence of PD is largely sporadic, mutations in five distinct genes have been linked to clinical syndromes that are often indistinguishable from sporadic PD. Of these, mutations in the parkin, DJ-1, and PINK1 (PTEN induced kinase 1) genes are recessively inherited and include large exonic deletions or frame-shift truncations, suggesting a loss-of-function pathogenic mechanism (1-3).PINK1 was originally identified as a gene whose transcription was activated by the tumor suppressor PTEN in carcinoma cell lines (4). The PINK1 gene has eight exons spanning 1.8 kb and encodes 581 aa residues. The deduced amino acid sequence indicates that PINK1 contains a mitochondrial targeting motif (amino acids 1-34) and a kinase domain (amino acids 156-509) that is highly homologous to Ca 2ϩ /calmodulin-dependent kinases. Since the first report linking recessively inherited nonsense (W437X) and missense (G309D) mutations in PINK1 to familial PARK6 cases (3), large numbers (Ͼ30) of additional truncation and missense mutations have been identified in early-onset PD cases with or without family history (5-11). Genetic analysis revealed that homozygous and compound heterozygous mutatio...

show abstract

Early-onset parkinsonism associated with PINK1 mutations

Cited by 316 publications

References 25 publications

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

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

Genetics of Parkinson's Disease

Impaired dopamine release and synaptic plasticity in the striatum of PINK1 -deficient mice

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