Defects in the endolysosomal system are increasingly viewed as key pathological features of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease. An emerging hypothesis is that chronic endolysosomal defects occurring in these disorders compromise the degradative capacity of lysosomes, causing the aberrant accumulation of a variety of lysosomal cargoes that are targeted to these organelles generally through the endocytic or autophagy pathway. These cargoes not only include a range of aggregate-prone proteins or peptides (e.g., Abeta, aberrant alpha-synuclein and tau), but also lipids, such as cholesterol and sphingolipids. Recently, our lab has employed a systems-based approach called lipidomics to profile hundreds of lipids from healthy and diseased tissue using state-of-the-art mass spectrometry. With this technology, we identified a striking lipid alteration in vulnerable brain regions from patients with AD, in a mouse model of Niemann-Pick type C (NPC), an aggressive lysosomal storage disorder that shares some pathogenic processes in common with AD, as well as in other instances where apolipoprotein-derived cholesterol is aberrantly accumulating. This lipid is called lysobisphosphatidic acid (LBPA) or bis(monoacylglycero) phosphate, an atypical phospholipid that is specifically enriched in the multivesicular endosomes and lysosomes, where it is further concentrated on cholesterol-rich intralumenal vesicles (ILVs). LBPA has been previously suggested to promote the formation of ILVs in the endolysosomal compartment, to regulate the storage and distribution of apolipoprotein-derived cholesterol, and facilitate lysosomal degradation by stimulating hydrolases. Together with these studies, our lipidomic data not only identify LBPA as a candidate biomarker for disorders associated with endolysosomal dysfunction, but they also suggest a critical role for this phospholipid both in the physiology and the pathophysiology of these organelles as well as in the administration of apolipoprotein-derived cholesterol. Unfortunately, tools are currently lacking to understand the precise (patho)physiological roles of this endolysosomal lipid and manipulate its levels to assess its therapeutic potential. The primary reason behind this roadblock is that the enzymes mediating the synthesis and degradation of this elusive phospholipid are unknown. The main goals of this proposal are thus (i) to identify the LBPA-metabolizing enzymes and more generally, the genes positively or negatively regulating the levels of LBPA using a combination of genome-wide RNAi screen and lipidomics; and (ii) to assess the impact of various types of LBPA manipulations on lysosomal function in normal neurons as well as in neurons derived from Npc1 mutant mice. We anticipate that our studies will be critical to understand the role of LBPA in endolysosomal physiology with potentially major implications for disorders associated with lysosomal dysfunction.
Endolysosomal dysfunction is increasingly viewed as a key pathogenic process in a variety of neurological disorders, including Alzheimer's disease, Parkinson's disease and Lewy body disorders. In this grant application, we propose to delineate the function of a endolysosomal phospholipid called lysobisphosphatidic acid or LBPA, which we hypothesize may be a key player in the physiology and pathophysiology of these organelles. One of the main challenges will be to identify the enzymes and factors that control the metabolism of this lipid.