Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation

Apr 3, 2026bioRxiv : the preprint server for biology

Loss of a key cell cleanup process causes dry AMD-like eye damage in mice and can be improved by activating BK channels

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Selective dysfunction of chaperone-mediated autophagy (CMA) recapitulates AMD-like pathologies in knockout mice.

CMA dysfunction leads to the accumulation of lipid and protein deposits beneath the retinal pigment epithelium (RPE).
Knockout mice exhibit RPE atrophy, thickening of Bruch's membrane, and impaired autophagic activity.
Pharmacological activation of large-conductance Ca²⁺-activated K⁺ (BK) channels with GLA-1-1 enhances autophagosome-lysosome fusion.
Oral administration of GLA-1-1 significantly reduces structural, functional, and molecular retinal abnormalities in CMA-deficient mice.
These findings suggest that enhancing macroautophagy could compensate for CMA deficiency in dry AMD.

AI simplified

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in elderly individuals for which no effective treatments are currently available. The photoreceptor loss in dry AMD is secondary to the demise of the retinal pigment epithelium (RPE) cells. The accumulation of extracellular deposits, known as drusen, resulting in part from deficient lysosomal and autophagosomal degradation, is a key feature of dry AMD pathogenesis. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains proteostasis by targeting specific cytosolic proteins for lysosomal translocation and degradation. LAMP2A (lysosome-associated membrane protein 2A) functions as the key lysosomal receptor required for CMA. Usingknockout mouse, we show that selective CMA dysfunction recapitulates AMD-like pathologies, including sub-RPE lipid and protein deposits, RPE atrophy, Bruch's membrane thickening, and impaired autophagic activity. Furthermore, we identify large-conductance Ca²⁺-activated K⁺ (BK) channels as a therapeutic target for restoring autophagic activity. Mechanistically, pharmacological activation of BK channels with the small-molecule agonist GLA-1-1 enhances macroautophagy and stimulates autophagic flux by promoting autophagosome-lysosome fusion. Importantly, oral administration of GLA-1-1 in markedly attenuates structural, functional, and molecular retinal abnormalities in-deficient mice, suggesting that pharmacological activation of macroautophagy through facilitating autophagosome-lysosome fusion can partially compensate for CMA deficiency. Together, these findings demonstrate that pharmacological activation of macroautophagy can ameliorate the retinal phenotype resulting from CMA dysfunction and support BK channel activation by GLA-1-1 as a promising therapeutic strategy for dry AMD. Lamp2a Lamp2a

Full Text

Full text is available at the source.

View full text ↗

Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief