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Special Issue Editor

Special Issue Information

Dear Colleagues,

Lysosomal diseases (LD) comprise more than 50 inherited disorders caused by mutations in the genes encoding lysosomal enzymes or cofactors related to substrate degradation pathways.

The research exploring the lysosome's metabolic functions has led to our understanding the roles of cell signaling, metabolite sensing, and the pathways involved in cell death and survival that significantly contribute to disease pathology and progression. New cellular and molecular techniques powered by "omics" are leading to the development of disease-specific biomarkers for clinical use and advanced therapies for LDs, such as gene therapy, small-molecule/nanomedicine approaches, RNA silencing, and genome editing. These innovative approaches have the potential to revolutionize therapies by targeting the underlying genetic and molecular mechanisms of the diseases. Moreover, the advent of novel developments and emerging technologies makes it imperative to address the role of downstream pathways in LDs to pursue precision or individualized medicine for patients with LDs.

Therefore, this Special Issue will focus on the latest advances, technological breakthroughs, and innovative diagnostics tools and therapies that are changing the LD landscape. We invite researchers to expand upon the discussion regarding the role of cell signaling, metabolite regulation, and inflammatory and other pathways to gain a better understanding of the disease process.

We look forward to your contributions.

Dr. Margarita Ivanova
Guest Editor

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Keywords

lysosomal storage diseases
omics
autophagy
mitochondria
advance therapy
biomarkers
precision medicine
genetic diseases
epigenetics
neurodegeneration

Published Papers (2 papers)

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Research

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21 pages, 4624 KiB

Open AccessFeature PaperArticle

Heterologous HSPC Transplantation Rescues Neuroinflammation and Ameliorates Peripheral Manifestations in the Mouse Model of Lysosomal Transmembrane Enzyme Deficiency, MPS IIIC

by Xuefang Pan, Antoine Caillon, Shuxian Fan, Shaukat Khan, Shunji Tomatsu and Alexey V. Pshezhetsky

Cells 2024, 13(10), 877; https://doi.org/10.3390/cells13100877 - 20 May 2024

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Abstract

Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme incapable of free diffusion between the cells or their cross-correction, which limits development of therapies based on enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC (Hgsnat^P304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied using behavior test battery, starting from the age of 6 months. At the age of ~8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage, and other biomarkers of the disease. We found that the treatment corrected several behavior deficits including hyperactivity and reduction in socialization, but not memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1β, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with cells from a normal healthy donor. They also suggest that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology. Full article

(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)

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Review

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18 pages, 1470 KiB

Open AccessReview

Unveiling the Roles of Cysteine Proteinases F and W: From Structure to Pathological Implications and Therapeutic Targets

by Kristina Zdravkova, Olja Mijanovic, Ana Brankovic, Polina M. Ilicheva, Aleksandra Jakovleva, Jelena Karanovic, Milena Pualic, Dusan Pualic, Aleksandr A. Rubel, Lyudmila V. Savvateeva, Alessandro Parodi and Andrey A. Zamyatnin, Jr.

Cells 2024, 13(11), 917; https://doi.org/10.3390/cells13110917 (registering DOI) - 25 May 2024

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Abstract

Cysteine cathepsins F and W are members of the papain-like cysteine protease family, which have distinct structural features and functional roles in various physiological and pathological processes. This review provides a comprehensive overview of the current understanding of the structure, biological functions, and pathological implications of cathepsins F and W. Beginning with an introduction to these proteases, we delve into their structural characteristics and elucidate their unique features that dictate their enzymatic activities and substrate specificity. We also explore the intricate involvement of cathepsins F and W in malignancies, highlighting their role as potential biomarkers and therapeutic targets in cancer progression. Furthermore, we discuss the emerging roles of these enzymes in immune response modulation and neurological disorders, shedding light on their implications in autoimmune and neurodegenerative diseases. Finally, we review the landscape of inhibitors targeting these proteases, highlighting their therapeutic potential and challenges in clinical translation. This review brings together the diverse facets of cysteine cathepsins F and W, providing insights into their roles in health and disease and guiding future investigations for therapeutic advances. Full article

(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)

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