scholarly journals Lentiviral Vectors Expressing Chimeric NEDD4 Ubiquitin Ligases: An Innovative Approach for Interfering with Alpha-Synuclein Accumulation

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3256
Author(s):  
Stefania Vogiatzis ◽  
Michele Celestino ◽  
Marta Trevisan ◽  
Gloria Magro ◽  
Claudia Del Del Vecchio ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Small Molecule ◽  
Catalytic Domain ◽  
Lentiviral Vectors ◽  
Alpha Synuclein ◽  
Pathological Features ◽  
Consensus Motifs ◽  
The One ◽  
As Toxicity

One of the main pathological features of Parkinson’s disease (PD) is a diffuse accumulation of alpha-synuclein (aS) aggregates in neurons. The NEDD4 E3 Ub ligase promotes aS degradation by the endosomal–lysosomal route. Interestingly, NEDD4, as well as being a small molecule able to trigger its functions, is protective against human aS toxicity in evolutionary distant models. While pharmacological activation of E3 enzymes is not easy to achieve, their flexibility and the lack of “consensus” motifs for Ub-conjugation allow the development of engineered Ub-ligases, able to target proteins of interest. We developed lentiviral vectors, encoding well-characterized anti-human aS scFvs fused in frame to the NEDD4 catalytic domain (ubiquibodies), in order to target ubiquitinate aS. We demonstrate that, while all generated ubiquibodies bind to and ubiquitinate aS, the one directed against the non-amyloid component (NAC) of aS (Nac32HECT) affects aS’s intracellular levels. Furthermore, Nac32HECT expression partially rescues aS’s overexpression or mutation toxicity in neural stem cells. Overall, our data suggest that ubiquibodies, and Nac32HECT in particular, represent a valid platform for interfering with the effects of aS’s accumulation and aggregation in neurons.

scholarly journals Identification by Automated Screening of a Small Molecule that Selectively Eliminates Neural Stem Cells Derived from hESCs but Not Dopamine Neurons

PLoS ONE ◽  
2009 ◽  
Vol 4 (9) ◽  
pp. e7155 ◽  
Author(s):  
Yi Han ◽  
Aaron Miller ◽  
Julie Mangada ◽  
Ying Liu ◽  
Andrzej Swistowski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Small Molecule ◽  
Dopamine Neurons ◽  
Automated Screening

Discovery of a Small Molecule that Enhances Astrocytogenesis by Activation of STAT3, SMAD1/5/8, and ERK1/2 via Induction of Cytokines in Neural Stem Cells

2015 ◽  
Vol 7 (1) ◽  
pp. 90-99 ◽  
Author(s):  
Ha-Rim Lee ◽  
Farhanullah ◽  
JiSoo Lee ◽  
Rahul Jajoo ◽  
Sun-Young Kong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Small Molecule

scholarly journals Cereblon-Based Small-Molecule Compounds to Control Neural Stem Cell Proliferation in Regenerative Medicine

2021 ◽  
Vol 9 ◽  
Author(s):  
Tomomi Sato ◽  
Takumi Ito ◽  
Hiroshi Handa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Regenerative Medicine ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Brain Size ◽  
Therapeutic Effects ◽  
Sedative Drug

Thalidomide, a sedative drug that was once excluded from the market owing to its teratogenic properties, was later found to be effective in treating multiple myeloma. We had previously demonstrated that cereblon (CRBN) is the target of thalidomide embryopathy and acts as a substrate receptor for the E3 ubiquitin ligase complex, Cullin-Ring ligase 4 (CRL4CRBN) in zebrafish and chicks. CRBN was originally identified as a gene responsible for mild intellectual disability in humans. Fetuses exposed to thalidomide in early pregnancy were at risk of neurodevelopmental disorders such as autism, suggesting that CRBN is involved in prenatal brain development. Recently, we found that CRBN controls the proliferation of neural stem cells in the developing zebrafish brain, leading to changes in brain size. Our findings imply that CRBN is involved in neural stem cell growth in humans. Accumulating evidence shows that CRBN is essential not only for the teratogenic effects but also for the therapeutic effects of thalidomide. This review summarizes recent progress in thalidomide and CRBN research, focusing on the teratogenic and therapeutic effects. Investigation of the molecular mechanisms underlying the therapeutic effects of thalidomide and its derivatives, CRBN E3 ligase modulators (CELMoDs), reveals that these modulators provide CRBN the ability to recognize neosubstrates depending on their structure. Understanding the therapeutic effects leads to the development of a novel technology called CRBN-based proteolysis-targeting chimeras (PROTACs) for target protein knockdown. These studies raise the possibility that CRBN-based small-molecule compounds regulating the proliferation of neural stem cells may be developed for application in regenerative medicine.

scholarly journals Inducible Alpha-Synuclein Expression Affects Human Neural Stem Cells' Behavior

2018 ◽  
Vol 27 (14) ◽  
pp. 985-994 ◽  
Author(s):  
Jacopo Zasso ◽  
Mastad Ahmed ◽  
Alessandro Cutarelli ◽  
Luciano Conti
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Alpha Synuclein ◽  
Human Neural Stem Cells

scholarly journals Aberrant Expression of Circulating MicroRNA Leads to the Dysregulation of Alpha-Synuclein and Other Pathogenic Genes in Parkinson’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Meng Cai ◽  
Songshan Chai ◽  
Tao Xiong ◽  
Jun Wei ◽  
Weibing Mao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Neural Stem Cells ◽  
Regulatory Network ◽  
Target Genes ◽  
Alpha Synuclein ◽  
Related Gene ◽  
Human Neural Stem Cells

A group of circulating microRNAs (miRNAs) have been implicated in the pathogenesis of Parkinson’s disease. However, a comprehensive study of the interactions between pathogenic miRNAs and their downstream Parkinson’s disease (PD)-related target genes has not been performed. Here, we identified the miRNA expression profiles in the plasma and circulating exosomes of Parkinson’s disease patients using next-generation RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that the miRNA target genes were enriched in axon guidance, neurotrophin signaling, cellular senescence, and the Transforming growth factor-β (TGF-β), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) signaling pathways. Furthermore, a group of aberrantly expressed miRNAs were selected and further validated in individual patient plasma, human neural stem cells (NSCs) and a rat model of PD. More importantly, the full scope of the regulatory network between these miRNAs and their PD-related gene targets in human neural stem cells was examined, and the findings revealed a similar but still varied downstream regulatory cascade involving many known PD-associated genes. Additionally, miR-23b-3p was identified as a novel direct regulator of alpha-synuclein, which is possibly the key component in PD. Our current study, for the first time, provides a glimpse into the regulatory network of pathogenic miRNAs and their PD-related gene targets in PD. Moreover, these PD-associated miRNAs may serve as biomarkers and novel therapeutic targets for PD.

scholarly journals Neural stem cells derived from the developing forebrain of YAC128 mice exhibit pathological features of Huntington’s disease

2020 ◽  
Vol 53 (10) ◽  
Author(s):  
Endan Li ◽  
Hee Ra Park ◽  
Chang Pyo Hong ◽  
Younghoon Kim ◽  
Jiwoo Choi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pathological Features

scholarly journals Lentiviral Vectors Mediate Efficient and Stable Gene Transfer in Adult Neural Stem Cells In Vivo

2006 ◽  
Vol 0 (0) ◽  
pp. 060801084750007
Author(s):  
Martine Geraerts ◽  
Kristel Eggermont ◽  
Pilar Hernandez-Acosta ◽  
Jose-Manuel Garcia-Verdugo ◽  
Veerle Baekelandt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Transfer ◽  
Neural Stem Cells ◽  
Lentiviral Vectors ◽  
Stable Gene ◽  
Adult Neural Stem Cells
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