Uche Medoh

Essay

The missing piece

Solving the 50-year puzzle of BMP synthesis in neurodegeneration

MOLECULAR MEDICINE

Abstract

Neurodegenerative diseases often result from lysosomal dysfunction, where cells fail to properly degrade lipids. The lysosomal lipid bis(monoacylglycero)phosphate (BMP) promotes this breakdown and prevents toxic lipid accumulation, but how BMP is made has been unknown for over half a century. I identified that CLN5—a gene mutated in Batten disease—encodes the long-sought BMP synthase. Through lipidomic, biochemical, and cellular analyses, I demonstrated that CLN5 catalyzes the condensation of two lysophosphatidylglycerol molecules to generate BMP within lysosomes, revealing an unexpected biosynthetic capacity of lysosomes. Furthermore, I found that CLN5 deficiency causes severe BMP depletion, lipid accumulation, and neuronal dysfunction characteristic of Batten disease. My work opens therapeutic avenues for restoring BMP levels to treat Batten disease and potentially other neurodegenerative disorders linked to lysosomal dysfunction.

Biography

Uche Medoh received an undergraduate degree from Yale University and conducted his PhD and postdoctoral research at Stanford University. He started his laboratory at the Arc Institute in 2024, where his research focuses on discovering and characterizing protein-metabolite interactions that can be leveraged to modulate aging and age-related diseases.