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Basal activity of PINK1 and PRKN in cell models and rodent brain

Watzlawik, Jens O. ; Fiesel, Fabienne C. ; Fiorino, Gabriella ; Bustillos, Bernardo A. ; Baninameh, Zahra ; Markham, Briana N. ; Hou, Xu ; Hayes, Caleb S. ; Bredenberg, Jenny M. and Kurchaba, Nicholas W. , et al. (2023) In Autophagy
Abstract

The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific... (More)

The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials.

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@article{9579d3c1-2d62-4d9d-9dc2-e3b3c3491f99,
  abstract     = {{<p>The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials.</p>}},
  author       = {{Watzlawik, Jens O. and Fiesel, Fabienne C. and Fiorino, Gabriella and Bustillos, Bernardo A. and Baninameh, Zahra and Markham, Briana N. and Hou, Xu and Hayes, Caleb S. and Bredenberg, Jenny M. and Kurchaba, Nicholas W. and Fričová, Dominika and Siuda, Joanna and Wszolek, Zbigniew K. and Noda, Sachiko and Sato, Shigeto and Hattori, Nobutaka and Prasad, Asheeta A. and Kirik, Deniz and Fox, Howard S. and Stauch, Kelly L. and Goldberg, Matthew S. and Springer, Wolfdieter}},
  issn         = {{1554-8627}},
  keywords     = {{Mitophagy; parkin; Parkinson disease; PINK1; PRKN; ubiquitin}},
  language     = {{eng}},
  publisher    = {{Landes Bioscience}},
  series       = {{Autophagy}},
  title        = {{Basal activity of PINK1 and PRKN in cell models and rodent brain}},
  url          = {{http://dx.doi.org/10.1080/15548627.2023.2286414}},
  doi          = {{10.1080/15548627.2023.2286414}},
  year         = {{2023}},
}