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Leiva-Rodríguez T, Romeo-Guitart D, Herrando-Grabulosa M, et al. GRP78 Overexpression Triggers PINK1-IP. Biomedicines. 2021;9(8)doi: 10.3390/biomedicines9081039.
Leiva-Rodríguez, T., Romeo-Guitart, D., Herrando-Grabulosa, M., Muñoz-Guardiola, P., Polo, M., Bañuls, C., Petegnief, V., Bosch, A., Lizcano, J. M., Apostolova, N., Forés, J., & Casas, C. (2021). GRP78 Overexpression Triggers PINK1-IP. Biomedicines, 9(8), . https://doi.org/10.3390/biomedicines9081039
Leiva-Rodríguez, Tatiana, et al. "GRP78 Overexpression Triggers PINK1-IP." Biomedicines vol. 9,8 (2021). doi: https://doi.org/10.3390/biomedicines9081039
Leiva-Rodríguez T, Romeo-Guitart D, Herrando-Grabulosa M, Muñoz-Guardiola P, Polo M, Bañuls C, Petegnief V, Bosch A, Lizcano JM, Apostolova N, Forés J, Casas C. GRP78 Overexpression Triggers PINK1-IP. Biomedicines. 2021 Aug 18;9(8). doi: 10.3390/biomedicines9081039. PMID: 34440243; PMCID: PMC8391647.
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Biomedicines. 2021 Aug 18;9(8). doi: 10.3390/biomedicines9081039.

GRP78 Overexpression Triggers PINK1-IP.

Biomedicines

Tatiana Leiva-Rodríguez, David Romeo-Guitart, Mireia Herrando-Grabulosa, Pau Muñoz-Guardiola, Miriam Polo, Celia Bañuls, Valerie Petegnief, Assumpció Bosch, Jose Miguel Lizcano, Nadezda Apostolova, Joaquim Forés, Caty Casas

Affiliations

  1. Department of Cell Biology, Physiology and Immunology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain.
  2. Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 08193 Barcelona, Spain.
  3. Laboratory Hormonal Regulation of Brain Development and Functions-Team 8, Institut Necker Enfants-Malades (INEM), INSERM U1151, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.
  4. Department of Biochemistry and Molecular Biology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain.
  5. Service of Endocrinology University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46010 Valencia, Spain.
  6. Department of Brain Ischemia and Neurodegeneration, Institute for Biomedical Research of Barcelona (IIBB), Spanish Research Council (CSIC), Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), 08036 Barcelona, Spain.
  7. CIBERehd, Department de Farmacologia, Facultat de Medicina, Universitat de Valencia, 46010 Valencia, Spain.
  8. Hand and Peripheral Nerve Unit, Hospital Clínic i Provincial, Universitat de Barcelona, 08007 Barcelona, Spain.

PMID: 34440243 PMCID: PMC8391647 DOI: 10.3390/biomedicines9081039

Abstract

An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.

Keywords: GRP78/BiP; mitophagy; motoneurons; neurodegeneration; neuroprotection

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