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

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, LC3β, 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.

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling

“…Integrins interface with redox signaling by triggering oxidation and inhibition of phosphatases that dephosphorylate and inactivate FAK ( 82 ). In addition, loss of BVR in the cortex leads to the accumulation of oxidatively damaged proteins with impaired autophagy ( 83 ). As a result, both BVR and FAK are tightly linked to redox signaling.…”

Knockdown of FAM225B inhibits the progression of the hypertrophic scar following glaucoma surgery by inhibiting autophagy

“…Beclin-1 is an important autophagy mediator, which increases autophagy ( 40 ). Furthermore, it has been reported that ATG7 promotes autophagy ( 41 ), while p62 is negatively associated with the autophagy process ( 42 ). The results of the current study were consistent with the aforementioned findings, suggesting that knockdown of FAM225B could inhibit the progression of HS by inhibiting autophagy.…”

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling

“…As a result, both BVR and FAK are tightly linked to redox signaling. Additionally, loss of BVR in the cortex leads to the accumulation of oxidatively-damaged proteins with impaired autophagy ( 81 ). Interestingly, shRNA-mediated knockdown of BVR has been shown to impair LTP at CA3-CA1 synapses in hippocampal slices ( 82 ).…”