Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

Puschmann, Andreas; Fiesel, Fabienne C.; Caulfield, Thomas R.; Hudec, Roman; Ando, Maya; Truban, Dominika; Hou, Xu; Ogaki, Kotaro; Heckman, Michael G.; James, Elle D.; Swanberg, Maria; Jiménez-Ferrer, Itzia; Hansson, Oskar; Opala, Grzegorz; Siuda, Joanna; Boczarska-Jedynak, Magdalena; Friedman, Andrzej; Koziorowski, Dariusz; Rudzińska‐Bar, Monika; Aasly, Jan; Lynch, Timothy; Mellick, George D.; Mohan, Megha; Silburn, Peter A.; Sanotsky, Yanosh; Vilariño‐Güell, Carles; Farrer, Matthew J.; Chen, Li; Dawson, Valina L.; Dawson, Ted M.; Wszołek, Zbigniew K.; Ross, Owen A.; Springer, Wolfdieter

doi:10.1093/brain/aww261

Cited by 121 publications

(111 citation statements)

References 72 publications

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“…Mutations in PTEN-induced putative kinase 1 (PINK1) cause rare inherited forms of PD (Valente et al, 2004; Ricciardi et al, 2014), providing the first direct genetic evidence that mitochondrial dysfunction can cause PD. Heterozygous mutations in PINK1 are also a risk factor for sporadic PD (Puschmann et al, 2017). Most, if not all, PD-causing mutations in PINK1 disrupt PINK1's kinase function (Song et al, 2013), implicating that loss of PINK1 kinase activity causes PD.…”

Section: Introductionmentioning

confidence: 99%

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

Orr

Rutaganira

Roulet

et al. 2017

Neurochemistry International

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Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals.

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Section: Introductionmentioning

confidence: 99%

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

Orr

Rutaganira

Roulet

et al. 2017

Neurochemistry International

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“…This indicates that the decreased stability of PINK1 I368N can be masked by high expression levels and stability deficits can only be observed under endogenous or low level exogenous PINK1 expression. Our data show that high-level PINK1 overexpression can override important regulatory mechanisms 24) . Altogether these results show that while generation, processing and stability of PINK1 p.I368N are not impaired under basal conditions, specifically the mutant full-length form does not properly accumulate on the OMM upon mitochondrial stress.…”

Section: Protein Instability Of Pink1 Pi368n Is Masked Upon Overexprmentioning

confidence: 75%

“…The modeling of the full-length human PINK1 protein, NP_115785.1 (581 amino acid residues), has been described recently 24) . In brief, each individual domain was modeled as a separate unit and built into a composite full-length structure.…”

Section: Modeling Pink1 Structures and Refinementmentioning

confidence: 99%

“…Using homology modeling, we have recently generated a structural model of full-length PINK1 at an all-atom resolution 24) . To examine how mutation of I368 affects PINK1 structure, we performed MDS.…”

Section: Structural Changes Of the P I368n Mutation Distort The Atp-mentioning

confidence: 99%

“…In contrast, the mutant p.G411S is expressed and upon damage forms a dimer on the OMM similar to PINK1 wild type (WT) 24) . However, in addition to partial loss of its kinase activity, in a heterodimer with PINK1 WT, p. G411S also exerts a partial, dominant-negative effect.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The PINK1 p.I368N Mutation Affects Protein Stability and Kinase Activity with Its Structural Change

Ando

Fiesel

Hudec

et al. 2018

Juntendo Medical Journal

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Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

Lambourne

Mehellou

2018

ChemBioChem

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PINK1 is a ubiquitously expressed mitochondrial serine/threonine protein kinase that has emerged as a key player in mitochondrial quality control. This protein kinase came to prominence in the mid‐2000s, when PINK1 mutations were found to cause early onset Parkinson's disease (PD). As most of the PD‐related mutations occurred in the kinase domain and impaired PINK1′s catalytic activity, it was suggested that small molecules that activated PINK1 would maintain mitochondrial quality control and, as a result, have neuroprotective effects. Working on this hypothesis, a few small‐molecule PINK1 activators that offer critical insights and distinct approaches for activating PINK1 have been discovered. Herein, we briefly highlight the discovery of these small molecules and offer insight into the future development of small‐molecule PINK1 activators as potential treatments for PD.

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Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

Cited by 121 publications

References 72 publications

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

The PINK1 p.I368N Mutation Affects Protein Stability and Kinase Activity with Its Structural Change

Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

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