Emerging roles of microglial cathepsins in neurodegenerative disease

Lowry, Jessica R.; Klegeris, Andis

doi:10.1016/j.brainresbull.2018.02.014

Cited by 53 publications

(50 citation statements)

References 187 publications

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“…On the other hand, the cysteine CTSB and the aspartate CTSD result to be up-regulated in a variety of neurological disorders [184][185][186]. The protease CTSS is preferentially expressed in cells of the macrophage/monocyte lineage, and inflammation stimulates its secretion from the microglia and macrophages [185,187]. The involvement of microglial CTSB, CTSD, and CTSS in neurodegenerative diseases supports the view that microglia-driven neuroinflammation contributes to the progression of neurodegeneration in MPS I and IIIB [183,188,189].…”

Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 73%

“…Since CTSB is a crucial regulator of the NLRP3 inflammasome, it likely contributes to the inflammasome-dependent pathway involved in MPS neuroinflammation [183]. On the other hand, the cysteine CTSB and the aspartate CTSD result to be up-regulated in a variety of neurological disorders [184][185][186]. The protease CTSS is preferentially expressed in cells of the macrophage/monocyte lineage, and inflammation stimulates its secretion from the microglia and macrophages [185,187].…”

Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 99%

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Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 73%

Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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“…Robust genetic and pharma cological preclinical investigations have consistently showed that regulating cathepsin activity can favour ably improve pathological features in certain auto immune and inflammatory diseases. Inhibitors of several cathepsins (B, D, L, K and S) have been described 174,293 and their activity has been evaluated in rheumatic auto immune diseases (such as SLE, RA and SjS) and neuro degenerative disorders, notably in AD 294 (TABLe 4). Selective inhibition of cathepsin S with a potent active site inhibitor known as RO5461111 (Roche) mitigated disease in MRL/lpr lupus prone mice, by reducing prim ing of T and B cells by dendritic cells, and plasma cell generation 262 .…”

Section: Substrate Reduction Therapies and Small-molecule Chaperonesmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

522

374

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| 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.

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“…Cysteine cathepsins are also upregulated during human papillomaviruses HPV16-induced cervical carcinogenesis [47]. Microglia-expressed cathepsins B, D and S have been implicated in the pathogenesis of Alzheimer's disease [7]. The impaired activity of CTSB (cathepsin B) and CTSD (cathepsin D) genes cause saposin C-deficient fibroblasts, and the accumulation of autophagosomes, leading to a form of lysosomal disorder, the Gaucher disease [48].…”

Section: Types Of Cathepsins and Their Functional Specificitiesmentioning

confidence: 99%

“…The structures, distribution, substrate affinity, and the clinical significance of this enzyme family have been reviewed widely [7]. They are expressed on different cells throughout the body such as dermal fibroblasts, among others.…”

Section: Introductionmentioning

confidence: 99%

Cathepsins: Proteases that are vital for survival but can also be fatal

Patel

Homaei

El‐Seedi

et al. 2018

Biomedicine & Pharmacotherapy

165

108

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The state of enzymes in the human body determines the normal physiology or pathology, so all the six classes of enzymes are crucial. Proteases, the hydrolases, can be of several types based on the nucleophilic amino acid or the metal cofactor needed for their activity. Cathepsins are proteases with serine, cysteine, or aspartic acid residues as the nucleophiles, which are vital for digestion, coagulation, immune response, adipogenesis, hormone liberation, peptide synthesis, among a litany of other functions. But inflammatory state radically affects their normal roles. Released from the lysosomes, they degrade extracellular matrix proteins such as collagen and elastin, mediating parasite infection, autoimmune diseases, tumor metastasis, cardiovascular issues, and neural degeneration, among other health hazards. Over the years, the different types and isoforms of cathepsin, their optimal pH and functions have been studied, yet much information is still elusive. By taming and harnessing cathepsins, by inhibitors and judicious lifestyle, a gamut of malignancies can be resolved. This review discusses these aspects, which can be of clinical relevance.

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Emerging roles of microglial cathepsins in neurodegenerative disease

Cited by 53 publications

References 187 publications

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Lysosomes as a therapeutic target

Cathepsins: Proteases that are vital for survival but can also be fatal

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