Calpain-specific breakdown fragment in human drusen

Area of Science:

• Ophthalmology
• Cell Biology
• Biochemistry

Background:

• Extracellular drusen containing proteolytic fragments are hallmarks of aging and age-related macular degeneration (AMD).
• Localized hypoxia is a potential risk factor contributing to AMD pathogenesis.
• Calpains, a class of proteolytic enzymes, are hypothesized to cause retinal cell and retinal pigment epithelium (RPE) degeneration following hypoxia, but direct evidence in AMD is lacking.

Purpose of the Study:

• To identify calpain-cleaved proteins within drusen from human eyes.
• To investigate the presence of calpain activation markers in drusen associated with normal aging and AMD.

Main Methods:

• Analysis of 76 human eye drusen (nodular and soft) from normal and AMD donor eyes.
• Immunofluorescence staining for SBDP150, a specific marker of calpain activation (cleavage product of α-spectrin).
• Immunofluorescence staining for recoverin to identify photoreceptor cells.

Main Results:

• SBDP150 was detected in 80% of nodular drusen from normal eyes and 90% from AMD eyes.
• SBDP150 was present in 72% of soft drusen, predominantly from AMD eyes.
• The majority of both soft and nodular drusen from AMD donors exhibited positive staining for SBDP150.

Conclusions:

• SBDP150, a marker of calpain activation, was identified in human drusen for the first time.
• Results suggest calpain-induced proteolysis contributes to photoreceptor and/or RPE cell degeneration in aging and AMD.
• Calpain inhibitors represent a potential therapeutic strategy to mitigate AMD progression.