Biology subjects

Ghoochani, A.

Publications and source records attributed to Ghoochani, A..

2 recordsLinked to original sources

bioRxiv2026

The Batten disease gene product CLN6 is a glycerophosphoglycerol epimerase that establishes S,S-BMP stereochemistry

Bis(monoacylglycero)phosphate (BMP), a lysosomal phospholipid essential for lipid catabolism and cholesterol clearance, has a noncanonical S,S glycerol configuration found in no other mammalian phospholipid, a feature necessary for its stability in the lysosome. How cells invert glycerol stereochemistry to build S,S-BMP has remained unexplained since this configuration was discovered five decades ago. Here, we show that the endoplasmic reticulum-resident Batten disease protein CLN6 is a Ca2+-dependent epimerase that isomerizes glycerophosphoglycerol (GPG) from R,S-GPG to S,S-GPG. CLN6-deficient cells, mouse tissues, and patient samples predominantly contain R,S-GPG, S,R-lysophosphatidylglycerol (LPG), and R,S-BMP instead of their S,S counterparts, with a net depletion of BMP. Purified CLN6 catalyzes GPG epimerization in vitro, an activity abolished by a pathogenic substitution in its substrate-binding pocket. Consistently, exogenous S,S-GPG restores BMP synthesis and relieves lipid storage in CLN6-null cells. Our work establishes stereochemical commitment upstream of acylation, placing CLN6, CLN8, and CLN5 in sequence in BMP biosynthesis and unifying the lipid defect across these neurodegenerative disorders.

biochemistry↗

bioRxiv2024

Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder

Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of novel lysosomal proteins and reveal the diversity of the lysosomal composition across brain cell types. Notably, we discovered SLC45A1, mutations in which cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. Mechanistically, SLC45A1 plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. SLC45A1 deficiency depletes the V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as a LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution in the brain and its implications for neurodegeneration.

cell biology↗