The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches

Drobny, Alice; Huarcaya, Susy Prieto; Dobert, Jan Philipp; Kluge, Annika; Bunk, Josina; Schlothauer, Theresia; Zunke, Friederike

doi:10.1016/j.bbamcr.2022.119243

Cited by 41 publications

(37 citation statements)

References 242 publications

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“…Our results indicated that the virus can utilize other cathepsins or lysosomal proteases to infect neurons when cathepsin L is inhibited. For example, cathepsin B can also be involved in SARS-CoV-2 entry ( 35 ), and this protein is abundantly expressed in human neurons and neuron-like cells ( 43 ).…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase

Kettunen

Lesnikova

Räsänen

et al. 2023

J Virol

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Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase

Kettunen

Lesnikova

Räsänen

et al. 2023

J Virol

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“…We next used IHC to probe cathepsin D and cathepsin B, the two major lysosomal proteases that are involved in proteolysis of tau and other neurodegenerative proteins 38,39 . We found no significant change of either cathepsin D or cathepsin B immunoreactivity in any area including dorsal and ventral hippocampus and amygdala (Fig.…”

Section: Resultsmentioning

confidence: 99%

Altered tau in rTg4510 mice after a single interfaced CHIMERA traumatic brain injury

Cheng

Cheung

Kang

et al. 2022

Preprint

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Traumatic brain injury (TBI) in an established risk factor for neurodegenerative disease. In this report, we used the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) to study the effects of a single moderate-severe TBI in rTg4510 mice, a mouse model of tauopathy. Fifteen male rTg4510 mice were impacted at 4.0J at 4-mo of age using interfaced CHIMERA and compared to sham controls. Immediately after injury, moderate-severe TBI induced significant mortality (7/15; 47%), and a prolonged duration of loss of righting reflex. At 2-mo post-injury, surviving mice displayed significant histological evidence of microgliosis (Iba1) and axonal injury (Neurosilver). Western blotting showed that TBI mice had a reduced p-GSK-3β (S9):GSK-3β ratio, suggesting greater tau kinase activity. However, tauopathy in surviving TBI mice showed a divergent response, with 3/8 mice having a very low level of tau protein in brain lysates (i.e. lower than sham), and were thus analyzed separately from the other 5/8 TBI mice that maintained the expected level of total tau. Compared to sham controls, TBI mice with normal tau levels had increased p-tau (PHF1 and AT8), increased autophagolysosome accumulation (p62 and Cathepsin D) and decreased hippocampal size. These findings were not observed in TBI mice with low total tau levels. These observations suggest that TBI leads to chronic white matter injury and altered GSK-3β activity. However, post-injury tauopathy and autophagolysosome accumulation diverged in surviving mice through mechanisms that remain to be defined.

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“…In the endosomes of immune cells, they participate in both the innate and adaptative immune responses [ 32 , 33 , 34 , 35 , 36 ]. Deregulation of the expression or activity of cathepsins in the endolysosomes leads to impaired degradation of organelle cargos, resulting in the accumulation of substrates that may be responsible for various pathological conditions [ 3 , 8 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. These conditions include lysosomal storage diseases (LSD) such as neuronal ceroid lipofuscinosis [ 37 ]; galactosidases [ 38 ]; mucopolysaccharidoses [ 39 ] and Gaucher disease [ 40 ]; Alzheimer’s [ 41 , 42 ]; Parkinson’s and Huntington’s diseases [ 43 ]; type I diabetes [ 44 ]; auto-immune diseases [ 3 ]; and others [ 8 ].…”

Section: Classification Synthesis Cellular Localization and Physiopat...mentioning

confidence: 99%

The Key Role of Lysosomal Protease Cathepsins in Viral Infections

Scarcella

d’Angelo

Ciampa

et al. 2022

IJMS

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Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment, cathepsins are also found in the cytoplasm, nucleus, and extracellular space, where they are involved in cell signaling, extracellular matrix assembly/disassembly, and protein processing and trafficking through the plasma and nuclear membrane and between intracellular organelles. Ubiquitously expressed in the body, cathepsins play regulatory roles in a wide range of physiological processes including coagulation, hormone secretion, immune responses, and others. A dysregulation of cathepsin expression and/or activity has been associated with many human diseases, including cancer, diabetes, obesity, cardiovascular and inflammatory diseases, kidney dysfunctions, and neurodegenerative disorders, as well as infectious diseases. In viral infections, cathepsins may promote (1) activation of the viral attachment glycoproteins and entry of the virus into target cells; (2) antigen processing and presentation, enabling the virus to replicate in infected cells; (3) up-regulation and processing of heparanase that facilitates the release of viral progeny and the spread of infection; and (4) activation of cell death that may either favor viral clearance or assist viral propagation. In this review, we report the most relevant findings on the molecular mechanisms underlying cathepsin involvement in viral infection physiopathology, and we discuss the potential of cathepsin inhibitors for therapeutical applications in viral infectious diseases.

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The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches

Cited by 41 publications

References 242 publications

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase

Altered tau in rTg4510 mice after a single interfaced CHIMERA traumatic brain injury

The Key Role of Lysosomal Protease Cathepsins in Viral Infections

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