lysosomal storage diseases
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Abstract Background Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients’ quality of life. Methods Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people’s views and actions. The study was conducted through in-depth face-to-face semi-structured interviews. Results In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers. Conclusions Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life.

People with respiratory problems and people prone to decompensations are particularly vulnerable to COVID-19. These characteristics are often present in patients with inherited metabolic diseases (IMDs). It is therefore conceivable that patients with IMDs are at a greater risk of infection and may present a more serious form of COVID-19 disease. Currently available data about the impact of COVID-19 on patients suffering from IMDs are very scarce and no study has been able to confirm this hypothesis. In this chapter, the authors have tried to show that the severity of COVID-19 infection in patients with IMDs is specific to the group that the disease belongs. Indeed, lysosomal storage diseases caused by impaired degradation and accumulation of metabolites in lysosomes leads to dysfunction of lysosomal and possible impairment of the COVID-19 egress process. The fact that COVID-19 disease may be considered itself as an IMD was also discussed to highlight the interference which can exist between COVID-19 disease and IMDs in a patient.

Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

<p>Azasugars are structural analogues of carbohydrates whereby the oxygen in the heterocyclic ring is substituted for a nitrogen. These carbohydrates are an important class of compounds with medicinal bioactivities and have shown potential for the treatment of diabetes, viral-infection, cancers, and lysosomal storage diseases. 1-deoxymannojirimycin (DMJ), is a mannosidase inhibiting azasugar which has shown anti-cancer and anti-viral activity. There has been significant effort put towards developing methodology to produce this compound and libraries of its derivatives. This thesis presents the synthesis of DMJ and a selection of its derivatives via an efficient 4 step methodology from a carbohydrate starting material, exploiting chemo and regioselective reactions to allow for a total synthesis with minimal use of protecting groups. The synthesis of DMJ, using the methodology developed herein, surpasses published syntheses in efficiency. This synthetic strategy was then used for the preparation of N-functionalised DMJ derivatives without the requirement of additional synthetic steps. To illustrate the versatility of this methodology, a selection of derivatives incorporating different functionalities have been synthesised.</p>

<p>Azasugars are structural analogues of carbohydrates whereby the oxygen in the heterocyclic ring is substituted for a nitrogen. These carbohydrates are an important class of compounds with medicinal bioactivities and have shown potential for the treatment of diabetes, viral-infection, cancers, and lysosomal storage diseases. 1-deoxymannojirimycin (DMJ), is a mannosidase inhibiting azasugar which has shown anti-cancer and anti-viral activity. There has been significant effort put towards developing methodology to produce this compound and libraries of its derivatives. This thesis presents the synthesis of DMJ and a selection of its derivatives via an efficient 4 step methodology from a carbohydrate starting material, exploiting chemo and regioselective reactions to allow for a total synthesis with minimal use of protecting groups. The synthesis of DMJ, using the methodology developed herein, surpasses published syntheses in efficiency. This synthetic strategy was then used for the preparation of N-functionalised DMJ derivatives without the requirement of additional synthetic steps. To illustrate the versatility of this methodology, a selection of derivatives incorporating different functionalities have been synthesised.</p>

AbstractThe binding of the major stress-inducible human 70-kDa heat shock protein (Hsp70) to the anionic phospholipid bis-(monoacylglycero)-phosphate (BMP) in the lysosomal membrane is crucial for its impact on cellular pathology in lysosomal storage disorders. However, the conformational features of this protein-lipid complex remain unclear. Here, we apply hydrogen–deuterium exchange mass spectrometry (HDX-MS) to describe the dynamics of the full-length Hsp70 in the cytosol and its conformational changes upon translocation into lysosomes. Using wild-type and W90F mutant proteins, we also map and discriminate the interaction of Hsp70 with BMP and other lipid components of the lysosomal membrane. We identify the N-terminal of the nucleotide binding domain (residues 87–118) as the primary orchestrator of BMP interaction. We show that the conformation of this domain is significantly reorganized in the W90F mutant, explaining its inability to stabilize lysosomal membranes. Overall, our results reveal important new molecular details of the protective effect of Hsp70 in lysosomal storage diseases, which, in turn, could guide future drug development.

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

AbstractLysosome (L), a hydrolytic compartment of the endo-lysosomal system (ELS), plays a central role in the metabolic regulation of eukaryotic cells. Furthermore, it has a central role in the cytopathology of several diseases, primarily in lysosomal storage diseases (LSDs). Mucopolysaccharidosis II (MPS II, Hunter disease) is a rare LSD caused by idunorate-2-sulphatase (IDS) enzyme deficiency. To provide a new platform for drug development and clarifying the background of the clinically observed cytopathology, we established a human in vitro model, which recapitulates all cellular hallmarks of the disease. Some of our results query the traditional concept by which the storage vacuoles originate from the endosomal system and suggest a new concept, in which endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and RAB2/LAMP positive Golgi (G) vesicles play an initiative role in the vesicle formation. In this hypothesis, Golgi is not only an indirectly affected organelle but enforced to be the main support of vacuole formation. The purposes of this minireview are to give a simple guide for understanding the main relationships in ELS, to present the storage vacuoles and their relation to ELS compartments, to recommend an alternative model for vacuole formation, and to place the Golgi in spotlight of MPS II cytopathology.