| Title |
Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease
|
|---|---|
| Published in |
Acta Neuropathologica Communications, April 2017
|
| DOI | 10.1186/s40478-017-0431-y |
| Pubmed ID | |
| Authors |
Franc Llorens, Katrin Thüne, Beata Sikorska, Matthias Schmitz, Waqas Tahir, Natalia Fernández-Borges, Maria Cramm, Nadine Gotzmann, Margarita Carmona, Nathalie Streichenberger, Uwe Michel, Saima Zafar, Anna-Lena Schuetz, Ashish Rajput, Olivier Andréoletti, Stefan Bonn, Andre Fischer, Pawel P. Liberski, Juan Maria Torres, Isidre Ferrer, Inga Zerr |
| Abstract |
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrP(Sc)). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca(2+)) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca(2+) responsive genes in sCJD brain tissue, accompanied by two Ca(2+)-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrP(Sc) in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca(2+) homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention. |
X Demographics
The data shown below were collected from the profiles of 4 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 25% |
| United States | 1 | 25% |
| Unknown | 2 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 75% |
| Scientists | 1 | 25% |
Mendeley readers
The data shown below were compiled from readership statistics for 53 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 53 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 8 | 15% |
| Researcher | 7 | 13% |
| Student > Bachelor | 6 | 11% |
| Student > Master | 4 | 8% |
| Student > Doctoral Student | 3 | 6% |
| Other | 11 | 21% |
| Unknown | 14 | 26% |
| Readers by discipline | Count | As % |
|---|---|---|
| Neuroscience | 12 | 23% |
| Biochemistry, Genetics and Molecular Biology | 5 | 9% |
| Agricultural and Biological Sciences | 5 | 9% |
| Medicine and Dentistry | 4 | 8% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 4% |
| Other | 9 | 17% |
| Unknown | 16 | 30% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 20 December 2017.
All research outputs
#14,344,573
of 22,968,808 outputs
Outputs from Acta Neuropathologica Communications
#1,082
of 1,390 outputs
Outputs of similar age
#172,438
of 309,813 outputs
Outputs of similar age from Acta Neuropathologica Communications
#21
of 25 outputs
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