Lysosomes as a therapeutic target

Abstract

Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases - including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease - this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

Fig. 1. The central position of lysosomes at the crossroads of major autophagic pathways.

a | Functional lysosomes are involved in the degradation (endocytic and autophagic) and regulation of exogenous and endogenous cellular material, including recycling processes. Extracellular material endocytosed by the endosomes and intracellular cargo internalized by the autophagosomes fuse with lysosomes for degradation, which produces energy (ATP production) and source molecules for the macromolecules. Mechanistic target of rapamycin complex 1 (mTORC1) plays a key role in lysosomal nutrient sensing signals (lysosome-to-nucleus axis) to regulate energy metabolism. Factors such as energy levels, type of pH, ion channel regulation and others decide the fate of the catabolic process. During lysosomal exocytosis, the lysosomal content favours plasma membrane (PM) repair, bone resorption, immune response and elimination of pathogenic stores. b | The lysosome is the ultimate cell compartment that digests unwanted protein materials generated by macroautophagy, microautophagy (pathways during which the cytoplasmic material is trapped in the lysosome by a process of membrane invagination) and chaperone-mediated autophagy (CMA). In general, lipid droplets (LDs) are degraded by lipophagy, a subtype of macroautophagy, which is activated by cytosolic lipases. CMA has also been demonstrated to participate in the degradation of LDs in which perilipin (PLIN2/3) proteins are phosphorylated (P) by AMP-activated protein kinase (AMPK) with the help of the HSPA8 chaperone. Mechanistic target of rapamycin complex 2 (mTORC2) and AKT (also known as protein kinase B) are negative regulators of CMA, where they exert their effect on the translocation complex of CMA. In situations of starvation, negative regulators are controlled by pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP). Lysosomal stability effects the transcription factor EB (TFEB) translation to the nucleus in which TFEB binds to the coordinated lysosomal expression and regulation (CLEAR) motifs to regulate the transcription of genes. EF1a, elongation factor 1a; Lys, lysosome; Rac1, Ras-related C3 botulinum toxin substrate 1.

Fig. 2. Lysosomal molecular sites and processes as possible targets for therapeutic strategies.

After their synthesis in the rough endoplasmic reticulum (RER), the substrates (cargo) that are intended to be degraded through the endo-lysosomal pathway are transported to lysosomes via the trans-Golgi network (TGN). Among the key enzymatic systems that are involved in the lysosomal enzyme transportation of cargos from Golgi to lysosomes, the best studied is the mannose-6-phosphate (M6P) receptor (MPR) system, which binds newly synthesized lysosomal hydrolases in the TGN and delivers them to pre-lysosomal compartments. A few components synthesized in the late Golgi compartment are delivered directly to lysosomes via the 3-alkaline phosphatase (ALP) pathway. Lysosomal components, such as enzymes (lytic enzymes and kinases), membrane-bound proteins/complexes (mechanistic target of rapamycin (mTOR)), transporters and ion channels (vacuolar-type proton adenosine triphosphatase (v-ATPase), TRPML1 and osteopetrosis associated transmembrane protein 1 (Ostm1)) and chaperone-mediated transportation are the best-known targeting sites for lysosomal dysfunction. As depicted in the figure, many pharmacological antagonists and agonists exert activities that potentially correct lysosomal dysfunction and therefore represent potential effective pharmacological tools. CLEAR, coordinated lysosomal expression and regulation; CQ, chloroquine; HCQ, hydroxychloroquine; mTORC1, mTOR complex 1; PtdIns(3,5)P2, phosphatidylinositol-3,5-bisphosphate; RAPTOR, regulatory-associated protein of mTOR; SER, smooth endoplasmic reticulum; TFEB, transcription factor EB.

Fig. 3. Structures of selected pharmacological molecules designed to correct lysosomal dysregulation in disease.

Small molecules and peptides highlighted in this figure are activators and inhibitors of lysosomal constituents targeting mechanistic target of rapamycin (mTOR), vacuolar-type proton adenosine triphosphatase (v-ATPase), TRPML1, PIK kinase and HSPA8. For details, see the text and accompanying tables.