SIRT1 activation with neuroheal is neuroprotective but SIRT2 inhibition with AK7 is detrimental for disconnected motoneurons

Cell Death & Disease
David Romeo-GuitartC Casas

Abstract

Sirtuin 1 (SIRT1) activity is neuroprotective, and we have recently demonstrated its role in the retrograde degenerative process in motoneurons (MNs) in the spinal cord of rats after peripheral nerve root avulsion (RA) injury. SIRT2 has been suggested to exert effects opposite those of SIRT1; however, its roles in neurodegeneration and neuron response after nerve injury remain unclear. Here we compared the neuroprotective potentials of SIRT1 activation and SIRT2 inhibition in a mouse model of hypoglossal nerve axotomy. This injury induced a reduction of around half MN population within the hypoglossal nucleus by a non-apoptotic neurodegenerative process triggered by endoplasmic reticulum (ER) stress that resulted in activation of the unfolded protein response mediated by IRE1α and XBP1 by 21 days post injury. Both SIRT1 activation with NeuroHeal and SIRT2 inhibition with AK7 protected NSC-34 motor neuron-like cells against ER stress in vitro. In agreement with the in vitro results, NeuroHeal treatment or SIRT1 overexpression was neuroprotective of axotomized hypoglossal MNs in a transgenic mouse model. In contrast, AK7 treatment or SIRT2 genetic depletion in mice inhibited damaged MN survival. To resolve the in vitro/in vivo di...Continue Reading

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Citations

Apr 24, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·David Romeo-GuitartCaty Casas
Nov 2, 2019·Cells·David Romeo-GuitartCaty Casas
Dec 31, 2020·Cells·Sara Marmolejo-Martínez-ArteseroCaty Casas
Feb 14, 2021·Cells·Sara Marmolejo-Martínez-ArteseroDavid Romeo-Guitart
Feb 23, 2021·Journal of Clinical Laboratory Analysis·Yun ZhangYan Zhang
Feb 19, 2021·Frontiers in Pharmacology·Ramu ManjulaFrancisco J Alcain
Mar 7, 2021·Biomolecules·Yuqing ZhangAndrew Keith Davey
Jul 3, 2021·International Journal of Molecular Sciences·Núria Gaja-CapdevilaMireia Herrando-Grabulosa
Aug 28, 2021·Biomedicines·Tatiana Leiva-RodríguezCaty Casas
Sep 1, 2020·Brain Research Bulletin·Nahanna Zimmermann Menezes CarvalhoAlexandre Leite Rodrigues Oliveira

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Methods Mentioned

BETA
transgenic
PCR
nuclear translocation
dissection

Software Mentioned

NeuroHeal
GraphPad Prism
ImageJ
Image Lab
Applied

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