scholarly journals The Ubiquitin Proteasome System Is a Key Regulator of Pluripotent Stem Cell Survival and Motor Neuron Differentiation

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 581 ◽  
Author(s):  
Monique Bax ◽  
Jessie McKenna ◽  
Dzung Do-Ha ◽  
Claire H. Stevens ◽  
Sarah Higginbottom ◽  
...  
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Ubiquitin Proteasome System ◽  
Neuron Differentiation ◽  
Stem Cell Survival ◽  
Ubiquitin Proteasome

The ubiquitin proteasome system (UPS) plays an important role in regulating numerous cellular processes, and a dysfunctional UPS is thought to contribute to motor neuron disease. Consequently, we sought to map the changing ubiquitome in human iPSCs during their pluripotent stage and following differentiation to motor neurons. Ubiquitinomics analysis identified that spliceosomal and ribosomal proteins were more ubiquitylated in pluripotent stem cells, whilst proteins involved in fatty acid metabolism and the cytoskeleton were specifically ubiquitylated in the motor neurons. The UPS regulator, ubiquitin-like modifier activating enzyme 1 (UBA1), was increased 36-fold in the ubiquitome of motor neurons compared to pluripotent stem cells. Thus, we further investigated the functional consequences of inhibiting the UPS and UBA1 on motor neurons. The proteasome inhibitor MG132, or the UBA1-specific inhibitor PYR41, significantly decreased the viability of motor neurons. Consistent with a role of the UPS in maintaining the cytoskeleton and regulating motor neuron differentiation, UBA1 inhibition also reduced neurite length. Pluripotent stem cells were extremely sensitive to MG132, showing toxicity at nanomolar concentrations. The motor neurons were more resilient to MG132 than pluripotent stem cells but demonstrated higher sensitivity than fibroblasts. Together, this data highlights the important regulatory role of the UPS in pluripotent stem cell survival and motor neuron differentiation.

Effective motor neuron differentiation of hiPSCs on a patch made of crosslinked monolayer gelatin nanofibers

2016 ◽  
Vol 4 (19) ◽  
pp. 3305-3312 ◽  
Author(s):  
Yadong Tang ◽  
Li Liu ◽  
Junjun Li ◽  
Leqian Yu ◽  
Francesco Paolo Ulloa Severino ◽  
...  
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Electrode Array ◽  
Plug And Play ◽  
Neuron Differentiation ◽  
Neuron Spike ◽  
Induced Pluripotent ◽  
Multi Electrode Array

A patch made of crosslinked monolayer nanofibers was used for motor neuron differentiation from human induced pluripotent stem cells and plug-and-play with a commercial multi-electrode array for neuron spike recording.

scholarly journals Rapid, efficient, and simple motor neuron differentiation from human pluripotent stem cells

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Daisuke Shimojo ◽  
Kazunari Onodera ◽  
Yukiko Doi-Torii ◽  
Yasuharu Ishihara ◽  
Chinatsu Hattori ◽  
...  
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Neuron Differentiation ◽  
Simple Motor

scholarly journals Generating Diverse Spinal Motor Neuron Subtypes from Human Pluripotent Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Rickie Patani
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Pluripotent Stem Cells ◽  
Muscular Atrophy ◽  
Human Pluripotent Stem Cells ◽  
Disease Models ◽  
Differential Vulnerability ◽  
Neuronal Diversification

Resolving the mechanisms underlying human neuronal diversification remains a major challenge in developmental and applied neurobiology. Motor neurons (MNs) represent a diverse pool of neuronal subtypes exhibiting differential vulnerability in different human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The ability to predictably manipulate MN subtype lineage restriction from human pluripotent stem cells (PSCs) will form the essential basis to establishing accurate, clinically relevantin vitrodisease models. I first overview motor neuron developmental biology to provide some context for reviewing recent studies interrogating pathways that influence the generation of MN diversity. I conclude that motor neurogenesis from PSCs provides a powerful reductionist model system to gain insight into the developmental logic of MN subtype diversification and serves more broadly as a leading exemplar of potential strategies to resolve the molecular basis of neuronal subclass differentiation within the nervous system. These studies will in turn permit greater mechanistic understanding of differential MN subtype vulnerability usingin vitrohuman disease models.

scholarly journals High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Qiuhao Qu ◽  
Dong Li ◽  
Kathleen R. Louis ◽  
Xiangzhen Li ◽  
Hong Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Pluripotent Stem Cells ◽  
High Efficiency ◽  
Human Pluripotent Stem Cells ◽  
Neuron Differentiation ◽  
Islet 1

scholarly journals A Monolayer System for the Efficient Generation of Motor Neuron Progenitors and Functional Motor Neurons from Human Pluripotent Stem Cells

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1127
Author(s):  
Alessandro Cutarelli ◽  
Vladimir A. Martínez-Rojas ◽  
Alice Tata ◽  
Ingrid Battistella ◽  
Daniela Rossi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Pluripotent Stem Cells ◽  
Disease Modelling ◽  
Disease Phenotypes ◽  
In Vitro Systems ◽  
Induced Pluripotent

Methods for the conversion of human induced pluripotent stem cells (hiPSCs) into motor neurons (MNs) have opened to the generation of patient-derived in vitro systems that can be exploited for MN disease modelling. However, the lack of simplified and consistent protocols and the fact that hiPSC-derived MNs are often functionally immature yet limit the opportunity to fully take advantage of this technology, especially in research aimed at revealing the disease phenotypes that are manifested in functionally mature cells. In this study, we present a robust, optimized monolayer procedure to rapidly convert hiPSCs into enriched populations of motor neuron progenitor cells (MNPCs) that can be further amplified to produce a large number of cells to cover many experimental needs. These MNPCs can be efficiently differentiated towards mature MNs exhibiting functional electrical and pharmacological neuronal properties. Finally, we report that MN cultures can be long-term maintained, thus offering the opportunity to study degenerative phenomena associated with pathologies involving MNs and their functional, networked activity. These results indicate that our optimized procedure enables the efficient and robust generation of large quantities of MNPCs and functional MNs, providing a valid tool for MNs disease modelling and for drug discovery applications.

scholarly journals Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 571 ◽  
Author(s):  
Emily R. Seminary ◽  
Stephanie Santarriaga ◽  
Lynn Wheeler ◽  
Marie Mejaki ◽  
Jenica Abrudan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Induced Pluripotent Stem Cells ◽  
Motor Neurons ◽  
Pluripotent Stem Cells ◽  
Identical Twins ◽  
Sporadic Als ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.

scholarly journals Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Asako Otomo ◽  
Lei Pan ◽  
Shinji Hadano
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Protein Misfolding ◽  
Disease Onset ◽  
Ubiquitin Proteasome System ◽  
Protective Role ◽  
Motor Neuron Diseases ◽  
Ubiquitin Proteasome ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

scholarly journals Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cells

2014 ◽  
Vol 13 (6) ◽  
pp. 599-604 ◽  
Author(s):  
Yubing Sun ◽  
Koh Meng Aw Yong ◽  
Luis G. Villa-Diaz ◽  
Xiaoli Zhang ◽  
Weiqiang Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Neuron Differentiation
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