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BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain-Implications for Neurodegeneration

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2020

Antioxidants (Basel). 2020 Jul 27;9(8):671. doi: 10.3390/antiox9080671.

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain-Implications for Neurodegeneration

Lanzillotta C;Zuliani I;Vasavda C;Snyder SH;Paul BD;Perluigi M;Domenico FDD;Barone E

Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, 00185 Rome, Italy. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, 21205 MD, USA. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, 21205 MD, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, 21205 MD, USA.

Service type: Knockout mice

Abstract

Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our study was to clarify the role for BVR-A in the regulation of the mTOR/autophagy axis by evaluating age-associated changes (2, 6 and 11 months) in cerebral cortex samples collected from BVR-A knock-out (BVR-A-/-) and wild-type (WT) mice. Our results show that BVR-A deficiency leads to the accumulation of oxidatively-damaged proteins along with mTOR hyper-activation in the cortex. This process starts in juvenile mice and persists with aging. mTOR hyper-activation is associated with the impairment of autophagy as highlighted by reduced levels of Beclin-1, LC3, LC3II/I ratio, Atg5-Atg12 complex and Atg7 in the cortex of BVR-A-/- mice. Furthermore, we have identified the dysregulation of AMP-activated protein kinase (AMPK) as a critical event driving mTOR hyper-activation in the absence of BVR-A. Overall, our results suggest that BVR-A is a new player in the regulation of autophagy, which may be targeted to arrive at novel therapeutics for diseases involving impaired autophagy. Keywords: AMPK; autophagy; biliverdin reductase; mTOR; neurodegeneration; oxidative stress.

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