Insights in progressive myoclonus epilepsy: HSP70 promotes cystatin B polymerization

Rispoli, Ada; Cipollini, Elena; Catania, Sandra; Giaimo, Rossella Di; Pulice, Giuseppe; Houte, Stineke van; Sparla, Francesca; Piaz, Fabrizio Dal; Roncarati, Davide; Trost, Paolo; Melli, Marialuisa

doi:10.1016/j.bbapap.2013.09.011

Cited by 15 publications

(18 citation statements)

References 30 publications

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“…As expected, some of these proteins belong to biological processes that were already described for the EPM1 disease like oxido‐reduction stress (Lehtinen et al , ; Butinar et al , ; Fig J). Besides, oligomerization and aggregation of CSTB have been reported as sensitive to redox status of the environment (Ceru et al , ; Rispoli et al , ). However, we found de‐regulated biological processes, namely secretion, cell–cell adhesion, and protein–lipid assembly, that indicate a general effect of CSTB deficiency on the mechanisms affecting secretory pathways and cell–cell contact.…”

Section: Resultsmentioning

confidence: 99%

“…On the contrary, the overexpression of another protein of the same cystatin family, cystatin C, rescues degenerating neurons in the Cstb ‐KO mouse model (Kaur et al , ). Through a yeast two‐hybrid system, we have isolated several cytoplasmic proteins that specifically bind Cstb and are involved in cytoskeletal functions and not antiproteolytic function (Di Giaimo et al , ; Riccio et al , ; Rispoli et al , ) Alternative roles, apart from the inhibition of cathepsins, have been described in astrocytes isolated from Cstb ‐KO mice showing increased autophagy (Polajnar et al , ). A possible function of Cstb in vesicular trafficking and synapse physiology has been proposed by gene expression analyses of granule neurons from Cstb ‐KO mouse (Joensuu et al , ) and, recently, by studies on the involvement of CSTB in synaptic plasticity (Penna et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Cystatin B is essential for proliferation and interneuron migration in individuals with EPM 1 epilepsy

et al. 2020

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Progressive myoclonus epilepsy (PME) of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro in human cerebral organoids (hCOs) derived from EPM1 patients. We find that CSTB (but not one of its pathological variants) is secreted into the mouse cerebral spinal fluid and the conditioned media from hCOs. In embryonic mouse brain, we find that functional CSTB influences progenitors' proliferation and modulates neuronal distribution by attracting interneurons to the site of secretion via cell-non-autonomous mechanisms. Similarly, in patient-derived hCOs, low levels of functional CSTB result in an alteration of progenitor's proliferation, premature differentiation, and changes in interneurons migration. Secretion and extracellular matrix organization are the biological processes particularly affected as suggested by a proteomic analysis in patients' hCOs. Overall, our study sheds new light on the cellular mechanisms underlying the development of EPM1.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cystatin B is essential for proliferation and interneuron migration in individuals with EPM 1 epilepsy

et al. 2020

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“…Therefore, the level of miR-16-1 has important applications in epilepsy and Japanese encephalitis. HSP70, as a molecular chaperone, plays an important role in protein damage and repair (17). In normal brain tissue there was slight HSP70 expression, in the systemic administration of kainic acid induced status epilepticus in brain tissue HSP70 expression significantly increased.…”

Section: Discussionmentioning

confidence: 99%

miR-16-1 expression, heat shock protein 70 and inflammatory reactions in astrocytes of mice with epilepsy induced by encephalitis B virus infection

Yao

Yang

et al. 2017

Experimental and Therapeutic Medicine

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The upregulation of miR-16-1 expression and heat shock protein 70 (HSP70) and inflammatory reaction mechanism in astrocytes of mice with epilepsy induced by encephalitis B virus infection were studied. Six-to-eight-week-old healthy male C57BL/6 mice received intraperitoneal injection of pilocarpine (320–340 mg/kg, 40 mg/ml) to induce status epilepsy. After 7 days, mice were inoculated with 100 µl Dulbecco's modified Eagle's medium (DMEM) in the neck, including 6.25×23 PFU Japanese encephalitis virus P3 wild strain. The experiment was divided into 4 groups, including, the healthy control group, the epilepsy model group, the model group + negative inoculation group and the virus infection group with 10 mice in each group. The healthy control group received intraperitoneal injection of the same amount of normal saline; the model group + negative inoculation group was injected with the same amount of DMEM without P3. One and three days after infection, 5 mice from each group were sacrificed, hippocampus tissues were obtained and astrocytes were isolated. After purification, glial fibrillary acidic protein was identified by immunohistochemical staining. Infected glial cells were detected by P3 antigen of immunofluorescence staining. RT-PCR method was used to detect the expression of miR-16-1 mRNA in astrocytes. Western blot analysis was used to detect the expression of HSP70. ELISA method was used to detect the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and nuclear factor-κB (NF-κB) inflammatory factors in tail vein blood. Level of expression of miR-16-1 mRNA, HSP70 as well as IL-6, TNF-α and NF-κB inflammatory factor levels of virus infected mice of 1 and 3 days were significantly higher (P<0.05) than those of model group and negative inoculation group and lowest in control group. In conclusion, the level of expression of miR-16-1 and HSP70 can be increased by the infection of Japanese encephalitis virus on the astrocytes of mice with epilepsy, to promote the expression of IL-6, TNF-α and NF-κB of inflammatory factors.

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“…At least 3 of the proteins were specific to the cerebellum: RACK‐1, NF‐L, and brain β‐spectrin . The same group showed that cystatin B oligomerization takes place by the chaperone HSP70 starting from native monomers and is dependent on Cu 2+ binding . Important datum in this context is that stefin B binds copper, which remains to be shown for cystatin C.…”

Section: What Is Known About the Alternative Functions Of Stefin B Anmentioning

confidence: 89%

Putative alternative functions of human stefin B (cystatin B): binding to amyloid‐beta, membranes, and copper

Žerovnik

2016

J of Molecular Recognition

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We describe studies performed thus far on stefin B from the family of cystatins as a model protein for folding and amyloid fibril formation studies. We also briefly mention our studies on aggregation of some of the missense EPM1 mutants of stefin B in cells, which mimic additional pathological traits (gain in toxic function) in selected patients with EPM1 disease. We collected data on the reported interactors of stefin B and discuss several hypotheses of possible cytosolic alternative functions.

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Insights in progressive myoclonus epilepsy: HSP70 promotes cystatin B polymerization

Cited by 15 publications

References 30 publications

Cystatin B is essential for proliferation and interneuron migration in individuals with EPM 1 epilepsy

Cystatin B is essential for proliferation and interneuron migration in individuals with EPM 1 epilepsy

miR-16-1 expression, heat shock protein 70 and inflammatory reactions in astrocytes of mice with epilepsy induced by encephalitis B virus infection

Putative alternative functions of human stefin B (cystatin B): binding to amyloid‐beta, membranes, and copper

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