Details

Autor(en) / Beteiligte

• Wang, Wei
• Lee, Sang Joon
• Scott, Patrick A.
• Lu, Xiaoqin
• Emery, Douglas
• Liu, Yongqin
• Ezashi, Toshihiko
• Roberts, Michael R.
• Ross, Jason W.
• Kaplan, Henry J.
• Dean, Douglas C.

Titel

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

Ist Teil von

• Cell reports (Cambridge), 2016-04, Vol.15 (2), p.372-385

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Most retinitis pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nighttime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE) and, thus, is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment-rich outer segments (OSs), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis. [Display omitted] •Rod degeneration in retinitis pigmentosa prevents glucose release from the RPE•Glucose induces Txnip in cones to direct outer segment synthesis•Glucose starvation in cones blocks this synthesis, diminishing central vision•Rod transplant or glucose replacement therapy restores cone function Wang et al. show RPE glucose release requires rod outer segment extension. Glucose induces Txnip in cones to direct outer segment synthesis. With rod degeneration in retinitis pigmentosa, cones starve for glucose causing outer segment loss and diminished central vision. Rod transplant or glucose therapy restores synthesis and cone function.