Potential of Stem Cell-Derived Motor Neurons for Modeling Amyotrophic Lateral Sclerosis (ALS)

2013 ◽  
pp. 75-91
Author(s):  
Derek H. Oakley ◽  
Gist F. Croft ◽  
Hynek Wichterle ◽  
Christopher E. Henderson
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Stem Cell ◽  
Motor Neurons ◽  
Lateral Sclerosis

Polyphenols and Stem Cells for Neuroregeneration in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 27 ◽  
Author(s):  
Shweta Goyal ◽  
Brashket Seth ◽  
Rajnish Kumar Chaturvedi
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Stem Cell ◽  
Motor Neurons ◽  
Dopaminergic Neurons ◽  
Dietary Polyphenols ◽  
Lateral Sclerosis

: Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders, pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.

scholarly journals Maximizing the Survival of Amyotrophic Lateral Sclerosis Patients: Current Perspectives

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Osama A. Khairoalsindi ◽  
Ahmad R. Abuzinadah
Keyword(s):  
Gene Therapy ◽  
Amyotrophic Lateral Sclerosis ◽  
Stem Cell ◽  
Cell Therapy ◽  
Motor Neurons ◽  
Stem Cell Therapy ◽  
The United States ◽  
Disease Modifying Drugs ◽  
Familial Form ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease that leads to loss of the upper and lower motor neurons. Almost 90% of all cases occur in the sporadic form, with the rest occurring in the familial form. The disease has a poor prognosis, with only two disease-modifying drugs approved by the United States Food and Drug Administration (FDA). The approved drugs for the disease have very limited survival benefits. Edaravone is a new FDA-approved medication that may slow the disease progression by 33% in a selected subgroup of ALS patients. This paper covers the various interventions that may provide survival benefits, such as early diagnosis, medications, gene therapy, stem cell therapy, diet, nutritional supplements, multidisciplinary clinics, and mechanical invasive and noninvasive ventilation. The recent data on masitinib, the role of enteral feeding, gene therapy, and stem cell therapy is discussed.

scholarly journals Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair

2020 ◽  
Vol 29 (13) ◽  
pp. 2200-2217 ◽  
Author(s):  
Nidaa A Ababneh ◽  
Jakub Scaber ◽  
Rowan Flynn ◽  
Andrew Douglas ◽  
Paola Barbagallo ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Stem Cell ◽  
Genome Editing ◽  
Motor Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Dementia Patient ◽  
Homology Directed Repair ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Abstract The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used to generate isogenic control lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and non-homologous end-joining by deleting the repeat region, with the risk of creating indels and genomic instability. In this study, we demonstrate complete correction of an induced pluripotent stem cell (iPSC) line derived from a C9orf72-HRE positive ALS/frontotemporal dementia patient using CRISPR/Cas9 genome editing and homology-directed repair (HDR), resulting in replacement of the excised region with a donor template carrying the wild-type repeat size to maintain the genetic architecture of the locus. The isogenic correction of the C9orf72 HRE restored normal gene expression and methylation at the C9orf72 locus, reduced intron retention in the edited lines and abolished pathological phenotypes associated with the C9orf72 HRE expansion in iPSC-derived motor neurons (iPSMNs). RNA sequencing of the mutant line identified 2220 differentially expressed genes compared with its isogenic control. Enrichment analysis demonstrated an over-representation of ALS relevant pathways, including calcium ion dependent exocytosis, synaptic transport and the Kyoto Encyclopedia of Genes and Genomes ALS pathway, as well as new targets of potential relevance to ALS pathophysiology. Complete correction of the C9orf72 HRE in iPSMNs by CRISPR/Cas9-mediated HDR provides an ideal model to study the earliest effects of the hexanucleotide expansion on cellular homeostasis and the key pathways implicated in ALS pathophysiology.

scholarly journals Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair

2019 ◽  
Author(s):  
Nidaa Ababneh ◽  
Jakub Scaber ◽  
Rowan Flynn ◽  
Andrew Douglas ◽  
Martin R. Turner ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Stem Cell ◽  
Genome Editing ◽  
Motor Neurons ◽  
Pluripotent Stem Cell ◽  
Intron Retention ◽  
Induced Pluripotent Stem Cell ◽  
Homology Directed Repair ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

AbstractThe G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used to generate isogenic control lines using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 and non-homologous end-joining (NHEJ) by deleting the repeat region with the risk of creating indels and genomic instability. In this study we demonstrate complete correction of an induced pluripotent stem cell (iPSC) line derived from a C9orf72-HRE positive ALS/FTD patient using CRISPR/Cas9 genome editing and homology directed repair (HDR), resulting in replacement of the excised region with a donor template carrying the wild-type repeat size to maintain the genetic architecture of the locus. The isogenic correction of the C9orf72 HRE restored normal expression and methylation at the C9orf72 locus, reduced intron retention in the edited lines, and abolished pathological phenotypes associated with the C9orf72 HRE expansion in iPSC derived motor neurons (iPSMNs).RNA sequencing of the mutant line identified 2220 differentially expressed genes compared to its isogenic control. Enrichment analysis demonstrated an over-representation of ALS relevant pathways, including calcium ion dependent exocytosis, synaptic transport and the KEGG ALS pathway, as well as new targets of potential relevance to ALS pathophysiology.Complete correction of the C9orf72 HRE in iPSMNs by CRISPR/Cas9 mediated HDR provides an ideal model to study the earliest effects of the hexanucleotide expansion on cellular homeostasis and the key pathways implicated in ALS pathophysiology.

Exploring molecular approaches in Amyotrophic lateral sclerosis: Drug targets from clinical and pre-clinical findings

2020 ◽  
Vol 13 ◽  
Author(s):  
Mamtaj Alam ◽  
Rajeshwar Kumar Yadav ◽  
Elizabeth Minj ◽  
Aarti Tiwari ◽  
Sidharth Mehan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Drug Targets ◽  
Therapeutic Index ◽  
Experimental Models ◽  
Clinical Findings ◽  
Adenyl Cyclase ◽  
Molecular Approaches ◽  
Pharmacologically Active ◽  
Lateral Sclerosis

: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterised by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age included impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% beyond 10 years of age. The limited intervention of pharmacologically active compounds that are used clinically is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, current review specially targeted in the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with up-regulation of intracellular adenyl cyclase/cAMP/CREB and mitochondrial-ETC coenzyme-Q10 activation as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.

Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 17 (3) ◽  
pp. 275-285 ◽  
Author(s):  
Si Chen ◽  
Qiao Liao ◽  
Ke Lu ◽  
Jinxia Zhou ◽  
Cao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rat Model ◽  
Microglial Activation ◽  
Transgenic Rat ◽  
Intragastric Administration ◽  
Behavioral Deficits ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

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