ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway

Retinal pigment epithelium (RPE) dysfunction and choroidal neovascularization (CNV) are predominant features of age-related macular degeneration (AMD), with an unclear mechanism. Herein, we show that RNA demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) is up-regulated in AMD. In RPE cells, ALKBH5 overexpression associates with depolarization, oxidative stress, disturbed autophagy, irregular lipid homeostasis, and elevated VEGF-A secretion, which subsequently promotes proliferation, migration, and tube formation of vascular endothelial cells. Consistently, ALKBH5 overexpression in mice RPE correlates with various pathological phenotypes, including visual impairments, RPE anomalies, choroidal neovascularization (CNV), and interrupted retinal homeostasis. Mechanistically, ALKBH5 regulates retinal features through its demethylation activity. It targets PIK3C2B and regulates the AKT/mTOR signaling pathway with YTHDF2 as the N6-methyladenosine reader. IOX1, an ALKBH5 inhibitor, suppresses hypoxia-induced RPE dysfunction and CNV progression. Collectively, we demonstrate that ALKBH5 induces RPE dysfunction and CNV progression in AMD via PIK3C2B-mediated activation of the AKT/mTOR pathway. Pharmacological inhibitors of ALKBH5, like IOX1, are promising therapeutic options for AMD.

 

Comments:

The passage you provided discusses a study indicating that the RNA demethylase ALKBH5 is upregulated in age-related macular degeneration (AMD) and plays a significant role in the development and progression of retinal pigment epithelium (RPE) dysfunction and choroidal neovascularization (CNV). Here's a breakdown of the key points in the passage:

1. **Background**: AMD is characterized by RPE dysfunction and CNV, but the mechanisms involved in these processes are not well understood.

2. **ALKBH5 Upregulation**: The study found that ALKBH5, an RNA demethylase, is increased in AMD.

3. **Effects of ALKBH5 Overexpression in RPE Cells**:
   - **Depolarization**: ALKBH5 overexpression leads to depolarization of RPE cells.
   - **Oxidative Stress**: RPE cells with elevated ALKBH5 experience oxidative stress.
   - **Disturbed Autophagy**: Autophagy, a cellular recycling process, is disrupted.
   - **Irregular Lipid Homeostasis**: Lipid balance in the cells is disturbed.
   - **Elevated VEGF-A Secretion**: Vascular Endothelial Growth Factor-A (VEGF-A) secretion is increased. VEGF-A promotes angiogenesis (formation of new blood vessels).
  
4. **Effects in Mice**:
   - **Pathological Phenotypes**: ALKBH5 overexpression in mice RPE leads to visual impairments, RPE anomalies, CNV, and disruption of retinal homeostasis.

5. **Mechanism of Action**:
   - **Demethylation Activity**: ALKBH5 affects retinal features through its demethylation activity.
   - **Target Gene**: It targets PIK3C2B and regulates the AKT/mTOR signaling pathway. YTHDF2 serves as the N6-methyladenosine reader in this process.

6. **Inhibition Studies**: IOX1, an inhibitor of ALKBH5, suppresses hypoxia-induced RPE dysfunction and CNV progression.

7. **Therapeutic Implications**: The findings suggest that pharmacological inhibitors of ALKBH5, such as IOX1, could be potential therapeutic options for AMD.

In summary, the study demonstrates that ALKBH5 overexpression induces RPE dysfunction and CNV progression in AMD by regulating the PIK3C2B-mediated activation of the AKT/mTOR pathway. Inhibitors like IOX1 show promise as potential treatments for AMD by targeting ALKBH5.

Related Products

Cat.No.	Product Name	Information
S7234	IOX1	IOX1 is a potent and broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases. IOX1 is an inhibitor of ALKBH5.

Related Targets

Histone Demethylase JMJD