Cardiolipin and Batten disease: investigating phospholipid alterations in ovine models

Abstract

Batten disease is a group of lysosomal storage disorders associated with mutations in 13 CLN genes causing neurodegeneration, brain atrophy, and juvenile mortality. Within the last decade considerable strides have been made in understanding CLN cellular biochemistry. Select CLN mutations result in lysosomal loss-of-function inhibiting bis (monoacylglycerol) phosphate (BMP) synthesis. Recent research may have advanced our understanding of CLN-associated lysosomal dysfunction – particularly as it relates to inhibition of BMP synthesis – yet little is known how this may affect extra-lysosomal phospholipids in other organelles. Given established phospholipid trafficking between the lysosomes, ER , and mitochondria, lysosomal perturbations may alter phospholipid metabolism in these organelles. We aim to characterise expression of mitochondrial phospholipid cardiolipin in ovine CLN5/CLN6 mutants to investigate whether disrupted BMP synthesis alters cardiolipin synthesis via their shared precursor, phosphatidyl glycerol. Phospholipid profiles of control and affected sheep will be examined by thin layer chromatographic and hyphenated mass spectrometric techniques to quantify the cardiolipin and related species. We hypothesise that CLN mutations generate excess phosphatidyl glycerol in the ER and mitochondria, causing an oversupply to the functional cardiolipin biosynthetic pathway. The resulting accumulation of cardiolipin in mitochondrial membranes may cause hallmark mitochondrial subunit c (SCMAS) accumulation in Batten disease. Validating this hypothesis would provide the first mechanistic description of SCMAS accumulation in Batten disease, linking lysosomal dysfunction with observed mitochondrial abnormalities, and offering new insight into the biochemistry of neurodegeneration for this disease