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Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors.

Rare diseases, or orphan diseases, are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), a cluster of rare metabolic diseases characterized by enzyme mutations causing abnormal glycolipid storage. Drug repositioning involves repurposing existing approved drugs for new therapeutic applications, offering advantages in cost, time savings, and a lower risk of failure. We present a comprehensive analysis of existing drugs, their repurposing potential, and their clinical implications in the context of LSDs, highlighting the necessity of mutation-specific approaches. Our review systematically explores the landscape of drug repositioning as a means to enhance LSDs therapies. The findings advocate for the strategic repositioning of drugs, accentuating its role in expediting the discovery of effective treatments. We conclude that drug repurposing represents a viable pathway for accelerating therapeutic discovery for LSDs, emphasizing the need for the careful evaluation of drug efficacy and toxicity in disease-specific contexts.

Table 1 Lysosomal storage disease causing cardiac disease Disease group and subtypes General manifestations Cardiac manifestations Glycogen storage diseases (lysosomal) Autosomal recessive Massive LVH and RVH, cardiac failure (only in the infantile form) Myopathy, hypotonia, hepatomegaly, macroglossia cardiopulmonary failure, Short PR, broad QRS; endomyocardial fibrosis Type IIb (Danon disease, LAMP-2 deficiency) X-linked Hypertrophic cardiomyopathy, isolated cardiac variants, short PR, progressive conduction system disease Myopathy, mental retardation Mucopolysaccharidoses IH (Hurler) Autosomal recessive Valvular involvement (thickening, regurgitation, stenosis); endomyocardial infiltration; interstitial infiltration-fibrosis; hypertrophy; systolic dysfunction-dilated cardiomyopathy (less frequent); coronary artery infiltration-stenosis; aortic stenosis (abdominal); arterial hypertension IS (Scheie) X-linked - MPS II (Hunter) II (Hunter) Dysmorphic features, organomegaly, decreased joint mobility, bone deformities, loss of motor skills, mental retardation, corneal clouding, recurrent otitis or pneumonia, hearing loss III (Sanfilippo) IV (Morquio) VI (Maroteaux-Lamy) VII (Sly) IX (Natowicz) Sphingolipidoses Gaucher disease (β-glucocerebrodiase) Autosomal recessive Pulmonary hypertension, cor pulmonale; pericardial effusion (rare); valvular involvement (rare) Chronic non-neuronopathic (type I) Gaucher cells-lipid laden macrophages Acute (type II) Hepatosplenomegaly, anaemia, thrombocytopenia, bone involvement Chronic neuronopathic (type III) Neurodegeneration (neuronopathic forms) Niemann Pick disease (acid sphingomyelinase) Autosomal recessive Endomyocardial fibrosis (very rare) Type A Early onset, neurological involvement, hypotonia, psychomotor retardation (type A), hepatosplenomegaly, pancytopenia, pulmonary involvement Type B Anderson-Fabry disease (α-galactosidase A) X-linked Cardiac hypertrophy; short PR, progressive conduction system dysfunction, arrhythmias; valvular involvement; coronary involvement (decreased coronary reserve) Multiorgan involvement LVH, left ventricular hypertrophy; RVH, right ventricular hypertrophy. [...]many studies have shown that affected women experience symptoms similar to hemizygous males, albeit in a milder form with a delayed onset and slower progression compared to men; similarly, the frequency of end-stage renal disease is much lower and the median cumulative survival greater (70 years vs 50 years) in women. 1 Disease expression in female patients is attributed to random X chromosome inactivation and the incapacity of cells expressing the wild-type allele to cross-correct the metabolic defect. 5 Pathogenesis of cardiac disease in AFD Cross-sectional data in patients of different ages suggest that disease evolution in the heart is characterised initially by myocardial hypertrophy; as the disease progresses interstitial abnormalities and replacement myocardial fibrosis become important.

Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal (“phagy”) functions, heightens the neuron’s vulnerability to genetic and environmental factors underlying Alzheimer’s disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy–lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-βCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aβ peptide. In the most compromised of these neurons, β-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an “inside-out” origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest “ intraneuronal ” stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets.

Background. Mesenteric lymphadenopathy is a rare manifestation of Gaucher disease (GD) in children and can be accompanied by protein losing enteropathy (PLE). PLE is a difficult-to-treat complication of GD. To date, only a few pediatric GD cases with PLE and massive mesenteric lymphadenopathies have been reported. Case. Here, we report a girl with chronic neuronopathic GD, whose disease course was complicated by massive mesenteric lymphadenopathies with resultant protein losing enteropathy despite a regular and appropriate enzyme replacement therapy of 60 IU/kg/biweekly until the development of mesenteric lymphadenopathies and 120 IU/kg/biweekly thereafter. Conclusions. PLE is a devastating and life threatening complication of GD developing despite long term use of high dose ERT. Clinicians should be alert for this complication particularly in GD patients presenting with progressive abdominal distension, edema, ascites and diarrhea or in patients who have already developed mesenteric lymphadenopathies. Timely diagnosis may allow early intervention with previously suggested surgical or medical treatment options. Although there is no specific and effective treatment, surgical and aggressive medical interventions in addition to ERT were reported to relieve diarrhea and halt progression of mesenteric lymphadenopathies.

The pathogenesis of Fabry disease is poorly understood. We used a variety of immunohistological techniques to localize globotriaosylceramide, the main glycolipid that accumulates in Fabry disease. Globotriaosylceramide immunoreactivity in a heterogenous pattern was present in all organs examined of a patient on long-term enzyme replacement therapy. In the brain, immmunopositivity was found only in the parahippocampal region. Globotriaosylceramide immunostaining was present in the cell membrane and cytoplasm of endothelial cells, even in the absence of lysosomal inclusions. In kidney tissue, globotriaosylceramide colocalized with lysosomal, endoplasmic reticulum, and nuclear markers. Pre- and postembedding immunogold electron microscopy of skin biopsies and untreated patient cultured skin fibroblasts confirmed the presence of globotriaosylceramide in the cell membrane, in various cytoplasmic structures, and in the nucleus. Control organ tissues and cultured fibroblasts from five unaffected subjects were uniformly negative for globotriaosylceramide by immunohistochemistry and immunogold electron microscopy. We conclude that a substantial amount of lysosomal and extralysosomal globotriaosylceramide immunoreactivity remains in cells and tissues even after years of enzyme replacement therapy in Fabry disease. These findings are crucial for the understanding of the disease mechanism and suggest the usefulness of immunostaining for globotriaosylceramide as a means to assess response to novel, specific therapies.

Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.

Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer’s and Parkinson’s disease, and lysosomal storage disorders.

Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann–Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal–lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics.