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Article ; Online: Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin

Abhisek Mukherjee / Karina Cuanalo-Contreras / Abha Sood / Claudio Soto

Biochemistry and Biophysics Reports, Vol 31, Iss , Pp 101311- (2022)

2022

Abstract: Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. ... ...

Abstract	Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required to reduce off-target effects, but its highly conserved active site and similar mechanism of action with other protein serine/threonine phosphatases impose a significant challenge. In this work, we developed a novel pharmacophore model to screen for CaN-specific inhibitors. Then, we performed a virtual screen for molecules having the pharmacophore model. We also show that the molecules identified in this screen can inhibit CaN with a low micromolar IC50. Interestingly, the inhibitors identified from the screen do not inhibit phosphoprotein phosphatase 2A, a member of the serine/threonine phosphatase family that shares 43% sequence identity with the CaN active site. The pharmacophore model that we developed and validated in this work may help to accelerate the development of specific CaN inhibitors.
Keywords	Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Subject code	500
Language	English
Publishing date	2022-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Uptake, Retention, and Excretion of Infectious Prions by Experimentally Exposed Earthworms

Sandra Pritzkow / Rodrigo Morales / Manuel Camacho / Claudio Soto

Emerging Infectious Diseases, Vol 27, Iss 12, Pp 3151-

2021 Volume 3154

Abstract: Prions are proteinaceous infectious agents that can be transmitted through various components of the environment, including soil particles. We found that earthworms exposed to prion-contaminated soil can bind, retain, and excrete prions, which remain ... ...

Abstract	Prions are proteinaceous infectious agents that can be transmitted through various components of the environment, including soil particles. We found that earthworms exposed to prion-contaminated soil can bind, retain, and excrete prions, which remain highly infectious. Our results suggest that earthworms potentially contribute to prion disease spread in the environment.
Keywords	prions and related diseases ; chronic wasting disease ; environmental transmission ; PMCA ; earthworms ; Medicine ; R ; Infectious and parasitic diseases ; RC109-216
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Centers for Disease Control and Prevention
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Preclinical Detection of Prions in Blood of Nonhuman Primates Infected with Variant Creutzfeldt-Jakob Disease

Luis Concha-Marambio / Marcelo A. Chacon / Claudio Soto

Emerging Infectious Diseases, Vol 26, Iss 1, Pp 34-

2020 Volume 43

Abstract: Variant Creutzfeldt-Jakob disease (vCJD) is caused by prion infection with bovine spongiform encephalopathy and can be transmitted by blood transfusion. Protein misfolding cyclic amplification (PMCA) can detect prions in blood from vCJD patients with 100% ...

Abstract	Variant Creutzfeldt-Jakob disease (vCJD) is caused by prion infection with bovine spongiform encephalopathy and can be transmitted by blood transfusion. Protein misfolding cyclic amplification (PMCA) can detect prions in blood from vCJD patients with 100% sensitivity and specificity. To determine whether PMCA enables prion detection in blood during the preclinical stage of infection, we performed a blind study using blood samples longitudinally collected from 28 control macaques and 3 macaques peripherally infected with vCJD. Our results demonstrate that PMCA consistently detected prions in blood during the entire preclinical stage in all infected macaques, without false positives from noninfected animals, when using the optimized conditions for amplification of macaque prions. Strikingly, prions were detected as early as 2 months postinoculation (>750 days before disease onset). These findings suggest that PMCA has the potential to detect vCJD prions in blood from asymptomatic carriers during the preclinical phase of the disease.
Keywords	prions ; variant Creutzfeldt-Jakob disease ; protein misfolding cyclic amplification ; diagnosis ; blood ; nonhuman primates ; Medicine ; R ; Infectious and parasitic diseases ; RC109-216
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Centers for Disease Control and Prevention
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction

Mauricio Torres / Karen Castillo / Ricardo Armisén / Andrés Stutzin / Claudio Soto / Claudio Hetz

PLoS ONE, Vol 17, Iss

Prion Protein Misfolding Affects Calcium Homeostasis and Sensitizes Cells to Endoplasmic Reticulum Stress

2022 Volume 1

Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson’s Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

Xiaojun Diao / Fei Wang / Andrea Becerra-Calixto / Claudio Soto / Abhisek Mukherjee

Cells, Vol 10, Iss 2402, p

2021 Volume 2402

Abstract: Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates ... ...

Abstract	Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene ( SNCA ) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.
Keywords	Parkinson’s disease ; iPSC ; dopaminergic neurons ; α-synuclein aggregates ; Lewy bodies ; mitochondria ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Altering Brain Amyloidosis by Intra-Lingual and Extra-Nasal Exposure of Aβ Aggregates

Nazaret Gamez / Javiera Bravo-Alegria / Yumeng Huang / Nelson Perez-Urrutia / Deepa Dongarwar / Claudio Soto / Rodrigo Morales

Cells, Vol 11, Iss 3442, p

2022 Volume 3442

Abstract: Extensive experimental and human-derived evidence suggest that misfolded Aβ particles spread similarly to infectious prions. Moreover, peripheral administration of Aβ seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. ...

Abstract	Extensive experimental and human-derived evidence suggest that misfolded Aβ particles spread similarly to infectious prions. Moreover, peripheral administration of Aβ seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aβ from the periphery to the brain are not fully understood, although circulation and retrograde axonal transport have been proposed. Here, we demonstrate that injection of Aβ seeds in the tongue, a highly innervated organ, substantially accelerates the appearance of plaques in Tg2576 mice. In addition, the extra-nasal exposure of Aβ aggregates increased amyloid pathology in the olfactory bulb. Our results show that exposing highly innervated tissues to Aβ seeds accelerates AD-like pathological features, and suggest that Aβ seeds can be transported from peripheral compartments to the brain by retrograde axonal transport. Research in this direction may be relevant on different fronts, including disease mechanisms, diagnosis, and risk-evaluation of potential iatrogenic transmission of Aβ misfolding.
Keywords	amyloid-beta ; Alzheimer’s disease ; prion ; tongue ; nasal cavity ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multi-Dose Intravenous Administration of Neutral and Cationic Liposomes in Mice

Stéphanie Andrade / Joana A. Loureiro / Santiago Ramirez / Celso S. G. Catumbela / Claudio Soto / Rodrigo Morales / Maria Carmo Pereira

Pharmaceuticals, Vol 15, Iss 761, p

An Extensive Toxicity Study

2022 Volume 761

Abstract: Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of ...

Abstract	Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often used in drug and gene delivery. For that purpose, adult wild-type mice (C57Bl6) were randomly distributed into three groups receiving either vehicle (PBS), neutral, or cationic liposomes and subjected to repeated intravenous injections for a total of 10 doses administered over 3 weeks. Several parameters, including mortality, body weight, and glucose levels, were monitored throughout the trial. While these variables did not change in the group treated with neutral liposomes, the group treated with the positively charged liposomes displayed a mortality rate of 45% after 10 doses of administration. Additional urinalysis, blood tests, and behavioral assays to evaluate impairments of motor functions or lesions in major organs were also performed. The cationic group showed less forelimb peak force than the control group, alterations at the hematological level, and inflammatory components, unlike the neutral group. Overall, the results demonstrate that cationic liposomes are toxic for multi-dose administration, while the neutral liposomes did not induce changes associated with toxicity. Therefore, our results support the use of the well-known neutral liposomes as safe drug shuttles, even when repetitive administrations are needed.
Keywords	lipid-based nanoparticles ; nanocarrier ; surface charge ; delivery systems ; chronic treatment ; mice ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	610
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Plasma Exchange Reduces Aβ Levels in Plasma and Decreases Amyloid Plaques in the Brain in a Mouse Model of Alzheimer’s Disease

Santiago Ramirez / Suelyn Koerich / Natalia Astudillo / Nicole De Gregorio / Rabab Al-Lahham / Tyler Allison / Natalia Pessoa Rocha / Fei Wang / Claudio Soto

International Journal of Molecular Sciences, Vol 24, Iss 23, p

2023 Volume 17087

Abstract: Alzheimer’s disease (AD) is the most common type of dementia, characterized by the abnormal accumulation of protein aggregates in the brain, known as neurofibrillary tangles and amyloid-β (Aβ) plaques. It is believed that an imbalance between cerebral ... ...

Abstract	Alzheimer’s disease (AD) is the most common type of dementia, characterized by the abnormal accumulation of protein aggregates in the brain, known as neurofibrillary tangles and amyloid-β (Aβ) plaques. It is believed that an imbalance between cerebral and peripheral pools of Aβ may play a relevant role in the deposition of Aβ aggregates. Therefore, in this study, we aimed to evaluate the effect of the removal of Aβ from blood plasma on the accumulation of amyloid plaques in the brain. We performed monthly plasma exchange with a 5% mouse albumin solution in the APP/PS1 mouse model from 3 to 7 months old. At the endpoint, total Aβ levels were measured in the plasma, and soluble and insoluble brain fractions were analyzed using ELISA. Brains were also analyzed histologically for amyloid plaque burden, plaque size distributions, and gliosis. Our results showed a reduction in the levels of Aβ in the plasma and insoluble brain fractions. Interestingly, histological analysis showed a reduction in thioflavin-S (ThS) and amyloid immunoreactivity in the cortex and hippocampus, accompanied by a change in the size distribution of amyloid plaques, and a reduction in Iba1-positive cells. Our results provide preclinical evidence supporting the relevance of targeting Aβ in the periphery and reinforcing the potential use of plasma exchange as an alternative non-pharmacological strategy for slowing down AD pathogenesis.
Keywords	Alzheimer’s disease ; plasma exchange ; albumin ; amyloid-β ; amyloid plaque ; plasmapheresis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	630
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease

Enrique Armijo / George Edwards / Andrea Flores / Jorge Vera / Mohammad Shahnawaz / Fabio Moda / Cesar Gonzalez / Magdalena Sanhueza / Claudio Soto

Cells, Vol 10, Iss 1802, p

2021 Volume 1802

Abstract: Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular ... ...

Abstract	Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.
Keywords	stem cells ; therapy ; Alzheimer’s disease ; amyloid-beta ; tau ; inflammation ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human Endogenous Retroviruses in Glioblastoma Multiforme

Zihao Yuan / Yuntao Yang / Ningyan Zhang / Claudio Soto / Xiaoqian Jiang / Zhiqiang An / Wenjin Jim Zheng

Microorganisms, Vol 9, Iss 764, p

2021 Volume 764

Abstract: Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor. It is primarily diagnosed in the elderly and has a 5-year survival rate of less than 6% even with the most aggressive therapies. The lack of biomarkers has made the development ... ...

Abstract	Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor. It is primarily diagnosed in the elderly and has a 5-year survival rate of less than 6% even with the most aggressive therapies. The lack of biomarkers has made the development of immunotherapy for GBM challenging. Human endogenous retroviruses (HERVs) are a group of viruses with long terminal repeat (LTR) elements, which are believed to be relics from ancient viral infections. Recent studies have found that those repetitive elements play important roles in regulating various biological processes. The differentially expressed LTR elements from HERVs are potential biomarkers for immunotherapy to treat GBM. However, the understanding of the LTR element expression in GBM is greatly lacking. Methods: We obtained 1077.4 GB of sequencing data from public databases. These data were generated from 111 GBM tissue studies, 30 GBM cell lines studies, and 45 normal brain tissues studies. We analyzed repetitive elements that were differentially expressed in GBM and normal brain samples. Results: We found that 48 LTR elements were differentially expressed ( p -value < 0.05) between GBM and normal brain tissues, of which 46 were HERV elements. Among these 46 elements, 34 significantly changed HERVs belong to the ERV1 superfamily. Furthermore, 43 out of the 46 differentially expressed HERV elements were upregulated. Conclusion: Our results indicate significant differential expression of many HERV LTR elements in GBM and normal brain tissues. Expression levels of these elements could be developed as biomarkers for GBM treatments.
Keywords	glioblastoma multiforme ; repetitive elements ; long terminal repeats ; human endogenous retrovirus ; brain ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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