Bastola, T. | bioRxiv Science

bioRxiv2024

Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress

Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is one of the key regulators of the cAMP/PKA signaling pathway. However, the precise molecular mechanisms underlying the sAC-mediated signaling pathway and mitochondrial protection in RGCs that counter oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress, we found that activating sAC protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death in a paraquat oxidative stress model. Notably, sAC activation ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

neuroscience↗

bioRxiv2023

Restoring AIBP deficiency in the retina provides neuroprotection in glaucoma

Glaucoma is a neurodegenerative disease manifested in retinal ganglion cell (RGC) death and irreversible blindness. While lowering intraocular pressure (IOP) is the only proven therapeutic strategy in glaucoma, it is insufficient for preventing disease progression, thus justifying the recent focus on targeting retinal neuroinflammation and preserving RGCs. We have identified apolipoprotein A-I binding protein (AIBP) as the protein regulating several mechanisms of retinal neurodegeneration. AIBP controls excessive cholesterol accumulation via upregulating the cholesterol transporter ATP-binding cassette transporter 1 (ABCA1) and reduces inflammatory signaling via toll-like receptor 4 (TLR4) and mitochondrial dysfunction. ABCA1, TLR4 and oxidative phosphorylation components are genetically linked to primary open-angle glaucoma. Here we demonstrated that AIBP and ABCA1 expression was decreased, while TLR4, interleukin 1 {beta} (IL-1{beta}), and the cholesterol content increased in the retina of patients with glaucoma and in mouse models of glaucoma. Restoring AIBP expression by a single intravitreal injection of adeno-associated virus (AAV)-AIBP protected RGCs in glaucomatous DBA/2J mice, in mice with microbead-induced chronic IOP elevation, and optic nerve crush. In addition, AIBP expression attenuated TLR4 and IL-1{beta} expression, localization of TLR4 to lipid rafts, reduced cholesterol accumulation, and ameliorated visual dysfunction. These studies collectively indicate that restoring AIBP expression in the glaucomatous retina reduces neuroinflammation and protects RGCs and Muller glia, suggesting the therapeutic potential of AAV-AIBP in human glaucoma. Significance StatementLowering intraocular pressure is insufficient to prevent progressive neuroinflammation, retinal ganglion cell (RGC) death and vision loss in glaucoma. We show that reduced expression of AIBP is associated with increased markers of neuroinflammation, TLR4 and IL-1{beta}, in human glaucomatous retina and mouse models of glaucoma. Restoring AIBP expression by an intravitreal injection of AAV-AIBP protects RGCs and preserves visual function in mouse models of glaucoma. Mechanistically, we demonstrate that AAV-AIBP disrupts TLR4-lipid raft formation and attenuates phosphorylation of AMPK, ERK1/2 and p38 and expression of TLR4 and IL-1{beta} in vivo. Collectively, our findings suggest that AIBP-mediated disruption of retinal TLR4-lipid rafts can prevent RGC loss and demonstrate the therapeutic potential of AAV-AIBP in treatment of human glaucoma.

neuroscience↗