Lysosomes play no part in determining which cells are eliminated. This is a function of the processes of programmed cell death apoptosis and phagocytosis. By bursting and releasing chemicals within the cell they were thought to bring about cell death and autolysis a word hardly used now. These functions, once attributed to lysosomes, no longer apply.
Research has shown that programmed cell death and phagocytosis is responsible for the elimination of cells. This happens throughout the life of an organism, but a striking example is seen during metamorphosis of tadpole to frog. Research on the endocytic pathway is indicating that lysosomes are storage organelles for hydrolases and that these are held in an inactive form.
Activation takes place when the lysosome fuses with a specific organelle to form a hybrid structure. Lysosomes lysosome: from the Greek: lysis; loosen and soma; body are found in nearly all animal and plant cells. In plant cells vacuoles can carry out lysosomal functions.
Lysosomes appear initially as spherical bodies about nm in diameter and are bounded by a single membrane. Several hundred lysosomes may be present in a single animal cell. Recent work suggests that there are two types of lysosomes: secretory lysosomes and conventional ones. Secretory lysosomes are found, although not exclusively, in different cells of the immune system, such as T lymphocytes, derived from the hemopoietic cell line.
Secretory lysosomes are a combination of conventional lysosomes and secretory granules. They differ from conventional lysosomes in that they contain the particular secretory product of the cell in which they reside. T lymphocytes for example contain secretory products perforin and granzymes that can attack both virus infected and tumour cells. The latter facility maintains an acidic environment in which the secretory products are maintained in an inactive form.
The mature secretory lysosomes move within the cytoplasm to the plasma membrane. This is all done with precise control of location and timing not only to maximise effect on the target but also to minimise collateral damage to friendly neighbouring cells. Some conventional cells e. Genetically driven disorders of secretory lysosomes can lead to impaired platelet synthesis, a type of immunodeficiency and hypopigmentation. Arrivals and meetings Lysosomes reside in the cell as re-usable organelles and when cell division takes place each daughter cell receives a number of lysosomes.
How this number is increased has not yet been elucidated. This is because white blood cells must digest more material than most other types of cells in their quest to battle bacteria, viruses, and other foreign intruders. Several human diseases are caused by lysosome enzyme disorders that interfere with cellular digestion. Tay-Sachs disease, for example, is caused by a genetic defect that prevents the formation of an essential enzyme that breaks down complex lipids called gangliosides.
An accumulation of these lipids damages the nervous system, causes mental retardation, and death in early childhood. Also, arthritis inflammation and pain are related to the escape of lysosome enzymes. License Info. Image Use.
Custom Photos. Site Info. Contact Us. The Galleries:. Photo Gallery. Silicon Zoo. Chip Shots. This iminosugar inhibits glucosylceramide synthase GCS , which catalyses the initial step in formation of many glycosphingolipids.
Within cells, glycosphingolipids tend to localize to the outer leaflet of the plasma membrane; they cycle within the cell through endocytic pathways that involve the lysosome. Inhibition of GCS therefore reduces the deleterious accumulation of glycosphingolipids within lysosomes with potential therapeutic benefits in diseases like LSDs. Miglustat also inhibits disaccharidases in the gastrointestinal tract, resulting in diarrhoea as a side effect Other GCS inhibitors in clinical development include lucerastat, a miglustat analogue with an improved safety profile that is currently in a phase III trial for Fabry disease FD , , and ibiglustat, which penetrates the CNS.
Recent findings generated in a small number of patients have suggested a possible link between PD and FD , which also exists between patients with PD and Gaucher disease who have GBA mutations see above. Finally, genistein, a pleotropic natural product that inhibits kinases involved in the regulation of proteoglycan biosynthesis and also affects TFEB function, is in a phase III trial for Sanfilippo syndrome Substrate mimetics that inhibit lysosomal enzymes have also been found to stabilize mutated enzymes in LSDs, thereby leading to restoration of some enzyme activity when suitable subinhibitory concentrations are used, as the enzyme remains stable and functional after dissociation of the inhibitor 46 , Other examples of this strategy include afegostat in Gaucher disease which failed in a phase II clinical trial in due to lack of efficacy , pyrimethamine in Sandhoff disease and Tay—Sachs disease, and ambroxol in Gaucher disease with neurological symptoms Table 4.
The chemical structures of these pharmacological chaperones have been described recently , Finally, an alternative strategy for stabilizing mutant enzymes, by binding away from the active site, is also being investigated. A promising example of this approach is NCGC, a non-inhibitory small-molecule chaperone of GCase discovered by screening for molecules that improved the activity of the mutant enzyme 46 , Although promising, conflicting viewpoints still remain on the strength of such small molecule-based approaches, primarily because these compounds bind to the catalytic site of enzymes, which may be a risk at high concentrations if they inhibit rather than increase activity , More clinical trials are therefore required in order to analyse the robustness of this approach.
Robust genetic and pharmacological preclinical investigations have consistently showed that regulating cathepsin activity can favourably improve pathological features in certain autoimmune and inflammatory diseases.
Promising data have also been generated in murine models, in the context of diabetic nephropathy and cardiovascular diseases Further studies based on cathepsin S inhibitors should evaluate the clinical safety and utility of treating patients affected by autoimmune and inflammatory diseases Cathepsin K, which is highly expressed by osteoclasts and very efficiently degrades type I collagen, the major component of the organic bone matrix, is also a potential target for modulating lysosomal dysfunction in some of the disorders discussed above, such as SLE Yet further investigations with selective cathepsin K inhibitors are required to determine whether this targeted strategy might apply in SLE and other inflammatory conditions in which articular manifestations are a major component RA, ankylosing spondylitis, psoriatic arthritis and others.
It should be noted, however, that various cathepsin K inhibitors have been pursued for postmenopausal osteoporosis, including odanacatib Merck which reached phase III trials Although odanacatib was effective, its development was discontinued in due to an increased risk of stroke in treated patients.
Other cathepsin inhibitors and their context of clinical evaluation are listed in Table 4. Despite multiple efforts to develop selective pharmacologic cathepsin modulators, important concerns still remain with regard to off-target effects due to activity against other cathepsins or towards cathepsins present at non-relevant or unwanted sites.
Nonetheless, the underlying biology and clinical effects of certain cathepsin inhibitors or activators remain of considerable interest and could guide future therapeutic approaches. As reported below, v-ATPase, a multisubunit ATP-driven proton pump, is best known for its role in acidification of endosomes and lysosomes.
Regulating the function of v-ATPase may impact lysosomal activity and, hence, the acidification of specialized cells and diverse signalling pathways, such as autophagy. Through this mechanism, bafilomycin A1 inhibits autophagic flux by preventing the acidification of endosomes and lysosomes Bafilomycin and CQ also affect mitochondrial functions, as discovered recently using intact neurons Benzolactoneenamides salicylihalamide A, lobatamides and oximidines; Table 4 ; Figs 2 , 3 are much more selective v-ATPase inhibitors than bafilomycin A1 and concanamycin A, but also much less potent.
Further investigations into v-ATPase regulation of signalling pathways are needed to identify specific and safe molecules that regulate this vital proton pump As discussed above, lysosomal ion channels are master elements of lysosome activity and, thereby, of cell homeostasis.
Thus, the small molecule SF Fig. An analogue of SF, in which chlorine on the thiophene had been replaced by a methyl group, showed greater efficacy on TRPML1 activation , It is important to note that in neurological diseases, as well as in other indications in which lysosomal acidification is defective see above , interfering with TRML1 may have contraindications.
The small-molecule apilimod Fig. It was well tolerated in more than human subjects normal healthy volunteers and patients with inflammatory disease , but the clinical trials did not meet their primary endpoints and further development was abandoned. Apilimod is currently being evaluated in a clinical trial NCT aimed at defining a maximum tolerated dose in patients with B cell non-Hodgkin lymphoma and monitoring safety, pharmacokinetics, pharmacodynamics and preliminary efficacy This inhibitor contains a FYVE-type zinc finger domain.
YM was found to significantly reduce the survival of primary mouse hippocampal neurons in culture and reversibly impair endosomal trafficking in NIH3T3 cells, mimicking the effect produced by depleting PIKfyve with small interfering RNA. It was also found to block retroviral exit by budding from cells From a clinical perspective, although targeting PIKfyve is highly promising, further work is required to pave a way towards a future treatment.
Several molecules with farnesyl transferase inhibitory activity have been developed. However, some earlier compounds were found to have major side effects, and their development was discontinued.
Lonafarnib SCH; Eiger Biopharmaceuticals , a synthetic tricyclic halogenated carboxamide, has recently shown some promise in a transgenic mouse, which expresses human tau carrying a PL mutation Table 4.
Compared with untreated mice, mice that received lonafarnib displayed less abnormal behaviour and half of the tangles in the hippocampi and cortices. Treatment also prevented brain atrophy that typically occurs in these transgenic mice, while reducing microgliosis in the hippocampus and tempering astrogliosis in the cortex.
Mechanistic studies have shown in lonafarnib-treated mice that substrates were more efficiently delivered to lysosomes, their degradation products disappeared faster and the organelles were more readily degraded, specifically by improving lysosome efficiency. Knowing that lonafarnib is already approved for use in humans for other indications cancer, and ongoing evaluation for progeria and hepatitis delta virus infection , it might therefore be repurposed for use in patients with tauopathy. Kura-oncology in-licenced tipifarnib in Molecules targeting chaperone proteins involved in lysosomal function have also been designed for potential therapeutic applications.
In a mouse model of AD 5XFAD mice , intraperitoneal treatment with VER reduced the two main pathological features of AD amyloid plaques and paired helical filament tau accumulation and improved object recognition, location and episodic-like memory Another molecule, the mer phosphopeptide P Table 4 ; Fig.
P and VER, however, do not have the same mechanism of action, and their effects were not additive As a downstream consequence, the activation of autoreactive B cells and their differentiation into autoantibody-secreting cells is repressed , In clinical trials that included patients with SLE, P formulated in mannitol was found to be safe and non-immunogenic after several subcutaneous administrations of peptide , , P showed significant efficacy in a multicentre, double-blind, phase II trial In continuation, an open-label trial including several hundred patients with lupus worldwide is planned.
Another peptide has been discovered that, in contrast to P, activates CMA This mer peptide called humanin was originally identified from surviving neurons in patients with AD, and was found to directly enhance CMA activity by increasing substrate binding and translocation into lysosomes.
Humanin interacts with HSP90 and stabilizes the binding of this chaperone to CMA cargos as they bind to the lysosomal membrane. These results are important as humanin had been shown to possess some cardioprotective and neuroprotective properties in diseases such as AD, cardiovascular disease, stroke, myocardial infarction, diabetes and cancer In addition to the targets discussed above, there are a few emerging potential lysosomal therapeutic targets for which there is strong biological validation, but not yet any small molecules in development that target them.
Importantly, the structure of TMEM has been recently refined It has been shown in NPC1 disease that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns Another promising therapeutic target is sphingomyelin phosphodiesterase 1 SMPD1. SMPD1 converts sphingomyelin to ceramide, and also has phospholipase C activity.
Reduced activity of acid sphingomyelinase, associated with a marked decrease in lysosomal stability, has been described in patients with Niemann—Pick disease, a phenotype that was corrected by treating cells with recombinant HSP70 Finally, as LAMP2A, a specific lysosomal protein that displays a decisive role in CMA, has been shown to be overexpressed in certain pathological settings such as certain cancers and inflammatory diseases autoimmune or non-autoimmune , downregulating its expression might be therapeutically beneficial 53 , Current research into lysosomal function and dysfunction is revealing novel roles of lysosomes in disease pathogenesis and highlighting new opportunities to treat such lysosomal and autophagy-related diseases.
As in the case of autophagy modulation 14 , 56 , , lysosomal activation or inhibition must be investigated with caution, as lysosomal activity can be abnormally reduced or enhanced in some organs or tissues and not in others, and, at another scale, lysosome activity can be altered in certain lysosomes and not in others within the same cell.
Biodistribution studies in vivo must be undertaken to avoid accumulation of pharmaceuticals in healthy organs or tissues. There is an obvious requirement for safety, to ensure that a drug used as a lysosome modulator for a particular type of lysosomal disease does not increase vulnerability to another disease. There is still much to be learned about the intimate working of lysosomes.
This is due to the abundance of constitutive elements that comprise these vesicles, the added complexity resulting from their plasticity ion channels and transporters, acidification and swelling and the vast amount of proteins and peptides that are translocated into lysosomes and digested by lytic enzymes. Sensitive analysis methods have allowed important information to be generated about lysosomal membrane proteins, a large majority of which are transporters 8. However, many questions remain related to how their expression is regulated and how they regulate their translocator and chaperoning activities.
For example, certain cells only contain so-called secretory lysosomes as in cytotoxic T cells , whereas other cell subsets contain both conventional and secretory lysosomes as in platelets. In many instances, lysosomes act as a basal cell metabolism organelle; whereas in other cases, they assist in the regulation of homeostasis through unconventional secretory pathways, known as lysosomal exocytosis, and different signalling mechanisms. Although several assays used to measure the activity of lysosomes have been validated worldwide Box 2 ; Table 3 , they have their limitations, including issues associated with reliability, performance and sensitivity, notably in vivo.
Another level of complexity comes from the inherent organelle heterogeneity, which is an issue of tremendous importance. Unfortunately, with the tools and equipment we have in hand today, it is virtually impossible to examine what happens in the lysosomes of an individual patient. The introduction of microfluidic single-cell analysis technologies has enabled cellular populations to be characterized and huge advances to be performed.
However, the level of precision has not yet been achieved at the level of lysosomes 0. Currently, this is obviously the focus of intense research. Although a certain number of preclinical studies involving lysosomal regulators have been conducted over the years, only a small number of lysosome-targeted therapeutics have so far moved into clinical development. One of the biggest advances in developing such strategies would be the identification of a genetic signature that would allow those patients most likely to respond to a specific therapy to be selected.
However, at this stage of our knowledge of specific lysosome-directed drugs and intrinsic lysosomal failures, genetic features that might predict potential responders are still lacking with the exception of LSDs. Further investigations are required to achieve this level of knowledge, which obviously will also depend on the type of disease, heterogeneity and frequency. Another issue associated with the development of lysosome-targeted therapeutics relates to delivery. The use of nanovectors represents an attractive delivery method, owing, in particular, to their unique ability to penetrate across cell barriers and, via the endo-lysosomal pathway, to preferentially home in on organelles such as lysosomes.
Several nanoscale galenic forms have been developed to serve as vectors or carriers of proteins, peptides or nucleic acids, and a vast literature describes the many advantages of using such nanostructures in nanomedicine. However, safety is a concern as some carbon nanostructures have been claimed to induce nanotoxicity, accompanied by the induction of autophagy and lysosomal dysfunction , , , reviewed elsewhere , , , The purpose of this Review is to gain awareness of the importance of lysosomes in disease, and to encourage the development of novel lysosomal targeted drugs.
However, more research is needed to characterize components that are specifically linked to the lysosome, such as LAMP2A and HSPA8, and to more clearly define their specific involvement in lysosome biogenesis and metabolism.
Special attention should be given to the mode of administration of lysosome-targeted medications in order to minimize toxicity and promote specific targeting. It is our hope that a large field of therapeutic applications could emerge from such investigations, encompassing rare and common autoimmune, neurodegenerative and metabolic diseases, as well as cancer, senescence and ageing.
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