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.

In Vivo Remodeling of Altered Autophagy-Lysosomal Pathway by a Phosphopeptide in Lupus

“…Our research has shown a consistent lysosomal malfunctioning in lupus splenocytes, manifested in the increase in endo/lysosomal volume, loss of acidification, reduced proteolytic activity against endocytosed substrates and TFEB expression. These lysosomal abnormalities have been simultaneously observed in aging, neurodegenerative diseases and other conditions where lysosomes are disordered or stressed [ 5 , 37 , 48 ]. However, our studies have revealed that the changes in the endo/lysosomal system in lupus-prone mice are much more complex than initially anticipated, likely due to the well-known heterogeneity of the various subsets of these compartments.…”

“…A number of activators and inhibitors of autophagy have been described [ 5 , 50 , 51 , 52 , 53 ]. In almost all cases, their fine specificity still remains to be determined.…”

“…It has long been recognized that lysosomes are at the heart of inflammation. In systemic lupus erythematosus (SLE), for instance, some defects have been described dealing with the composition and intrinsic activity of lysosomes that may affect the many functions of these central intracellular organelles [ 1 , 2 , 3 , 4 , 5 ]. In line with these observations, some autophagy alterations, mostly of macroautophagy, were demonstrated in the lymphocytes of two lupus-prone murine models of different major histocompatibility complex (MHC) haplotypes, namely Murphy Roths large/lymphoproliferation (hereafter named MRL/lpr) and (NZBxNZW)F1, as well as in the T and B lymphocytes of patients with lupus [ 6 , 7 , 8 , 9 ].…”

Adaptation of Proteasomes and Lysosomes to Cellular Environments

“…The lysosome can exhibit multiple tridimensional conformations, is highly dynamic, and is considered as a signaling hub because of its many possible functions [ 38 ]. The complex function stems partly from the 7–10 nm thick membrane that harbors 120 membrane-bound proteins not only maintaining intraluminal Na + , K + , Cl − , Ca 2+ ion concentrations and pH (pH~5) [ 39 ], but also selectively mobilizing and accepting cargo by for example, the Lysosome Associated Membrane Proteins (LAMP)-1-3 and Lysosomal Integral Membrane Protein (LIMP-2). Encapsulated within the lysosome are ~60 acid hydrolases (e.g., glycosidases, proteases, lipases, nucleases, phosphatases, and sulfatases) that are responsible for the degradation of nucleic acids, proteins, lipids and carbohydrates [ 40 ].…”

Irradiation pretreatment enhances the therapeutic efficacy of platelet-membrane- camouflaged antitumor nanoparticles

“…The lysosome is a membrane-coated acidic organelle that participates in the degradation and recycling of cellular waste, energy metabolism, and cell signaling transduction. Lysosomes are considered therapeutic targets to treat many diseases including lupus, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, and cancers [30,31]. Inhibiting lysosome function enhances the antitumor activity of chemotherapeutic drugs and increases the sensitivity of tumors to radiotherapy [32,33].…”