scholarly journals Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

2021 ◽  
Vol 14 (6) ◽  
pp. 565
Author(s):  
Yashashree Karpe ◽  
Zhenyu Chen ◽  
Xue-Jun Li
Keyword(s):  
Stem Cell ◽  
Motor Neuron ◽  
Gene Targeting ◽  
Motor Neurons ◽  
Gene Editing ◽  
Critical Role ◽  
Projection Neurons ◽  
Transcription Activator ◽  
Motor Neuron Diseases ◽  
Human Ipscs

Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.

scholarly journals Stem cell technology for the study and treatment of motor neuron diseases

2011 ◽  
Vol 6 (2) ◽  
pp. 201-213 ◽  
Author(s):  
J Simon Lunn ◽  
Stacey A Sakowski ◽  
Thais Federici ◽  
Jonathan D Glass ◽  
Nicholas M Boulis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Motor Neuron ◽  
Stem Cell Technology ◽  
Motor Neuron Diseases ◽  
Cell Technology

Motor Neuron Diseases

2014 ◽  
Author(s):  
Elena Ratti ◽  
Merit E. Cudkowicz ◽  
James D Berry
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Muscular Atrophy ◽  
Experimental Therapy ◽  
Rapid Progression ◽  
Motor Neuron Diseases ◽  
Efficacy Outcome ◽  
Single Disease Entity

The motor neuron diseases (MNDs) are a family of diseases commonly categorized by their propensity to affect upper or lower motor neurons and by their mode of inheritance. The chapter provides some content on infectious MNDs caused by viral infections affecting the motor neurons in the anterior horn of the spinal cord. However, the chapter devotes most of its attention to the inherited and sporadically occurring MNDs. The majority of research into adult MND focuses on amyotrophic lateral sclerosis (ALS) due to its high prevalence, rapid progression, and phenotypical similarities between its inherited form and its sporadic form. As our knowledge of genetic mechanisms underlying ALS pathology has grown, common themes have emerged. These include abnormalities in RNA biology, axonal transport, protein folding, and inflammatory responses. These themes currently drive much of the direction in ALS experimental therapy development. It is clear that MND is complex and involves several different molecular pathways. Given this complexity, ALS might not be a single disease entity, and if this is the case, treatment approaches may need to be targeted to specific pathologies rather than all ALS patients on a broad scale. Chapter content is enhanced by tables outlining the types of MNDs, criteria for supporting a diagnosis, first-line workup, the genes associated with ALS, ALS efficacy outcome measures, symptom management of ALS, and spinal muscular atrophy classification. Mechanisms of ALS are illustrated, and clinical photographs demonstrate symptoms. This chapter contains 252 references. 

Motor Neuron Diseases

2021 ◽  
pp. 752-759
Author(s):  
Eric J. Sorenson
Keyword(s):  
Motor Neuron ◽  
Incidence Rate ◽  
Motor Neurons ◽  
Anterior Horn Cell ◽  
Adult Onset ◽  
Motor Neuron Diseases ◽  
Kii Peninsula ◽  
Geographic Boundaries ◽  
Spinal Muscular Atrophies ◽  
Lateral Sclerosis

The motor neuron disorders are a clinically diverse group of diseases that share a pathologic loss of the motor neurons. The most common adult-onset disorder is amyotrophic lateral sclerosis (ALS). Other forms include the spinal muscular atrophies, infectious motor neuronopathies, and rare focal forms of anterior horn cell loss.Overall, the incidence rate of ALS is believed to be 1.5 to 2.0 cases per 100,000 person-years, and the prevalence rate is 4 to 6 cases per 100,000 population. Other than in sparsely populated geographic clusters (eg, Guam and the Kii Peninsula of Japan), the incidence rate seems consistent across ethnic and geographic boundaries.

scholarly journals A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

2020 ◽  
Vol 10 (3) ◽  
pp. 58 ◽  
Author(s):  
Owen Connolly ◽  
Laura Le Gall ◽  
Gavin McCluskey ◽  
Colette G Donaghy ◽  
William J Duddy ◽  
...  
Keyword(s):  
Systematic Review ◽  
Amyotrophic Lateral Sclerosis ◽  
Respiratory Failure ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Disease Duration ◽  
Phenotype Correlation ◽  
Motor Neuron Diseases ◽  
Relationship Of ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease’s genotype–phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.

Lower Motor Neuron Disease with Accumulation of Neurofilaments in a Cat

1976 ◽  
Vol 13 (6) ◽  
pp. 428-435 ◽  
Author(s):  
M. Vandevelde ◽  
C. E. Greene ◽  
E. J. Hoff
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Histological Examination ◽  
Muscle Atrophy ◽  
Motor Neurons ◽  
Nerve Cells ◽  
Lower Motor Neuron ◽  
Motor Neuron Diseases ◽  
Lower Motor Neuron Disease

A young cat had signs of tetraparesis that progressed to tetraplegia within a few weeks. Clinically, there was lower motor neuron disease with areflexia and muscle atrophy in all limbs. Degeneration of the motor neurons in the spinal cord was seen on histological examination. Ultrastructurally, the degeneration of nerve cells was characterized by abnormal proliferation of neurofilaments. These findings were compared to other motor neuron diseases and neurofibrillary accumulations in man and animals.

scholarly journals Impaired Autophagy in Motor Neurons: A Final Common Mechanism of Injury and Death

Physiology ◽  
2018 ◽  
Vol 33 (3) ◽  
pp. 211-224 ◽  
Author(s):  
Maria A. Gonzalez Porras ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Common Mechanism ◽  
Mechanism Of Injury ◽  
Therapeutic Approaches ◽  
Motor Neuron Diseases ◽  
Digestion Process ◽  
Cord Injury ◽  
Recent Developments ◽  
Health And Disease

Autophagy is a cellular digestion process that contributes to cellular homeostasis and adaptation by the elimination of proteins and damaged organelles. Evidence suggests that dysregulation of autophagy plays a role in neurodegenerative diseases, including motor neuron disorders. Herein, we review emerging evidence indicating the roles of autophagy in physiological motor neuron processes and its function in specific compartments. Moreover, we discuss the involvement of autophagy in the pathogenesis of motor neuron diseases, including spinal cord injury and aging, and recent developments that offer promising therapeutic approaches to mitigate effects of dysregulated autophagy in health and disease.

Retrograde transport and differential accumulation of serum proteins in motor neurons: Implications for motor neuron diseases

Neurology ◽  
1987 ◽  
Vol 37 (5) ◽  
pp. 843-843 ◽  
Author(s):  
T. Yamamoto ◽  
Y. Iwasaki ◽  
H. Konno ◽  
H. Iizuka ◽  
J.-X. Zhao
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Serum Proteins ◽  
Retrograde Transport ◽  
Motor Neuron Diseases

scholarly journals Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

PLoS Genetics ◽  
2017 ◽  
Vol 13 (3) ◽  
pp. e1006680 ◽  
Author(s):  
Rachel A. Kline ◽  
Kevin A. Kaifer ◽  
Erkan Y. Osman ◽  
Francesco Carella ◽  
Ariana Tiberi ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Alpha Synuclein ◽  
Motor Neuron Diseases

scholarly journals Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ya-Ping Yen ◽  
Wen-Fu Hsieh ◽  
Ya-Yin Tsai ◽  
Ya-Lin Lu ◽  
Ee Shan Liau ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Motor Neurons ◽  
Neural Development ◽  
Hox Genes ◽  
Critical Role ◽  
Embryonic Stem ◽  
Cell Types ◽  
Aberrant Expression ◽  
Spinal Cord Development

The mammalian imprinted Dlk1-Dio3 locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, including Meg3 (i.e., Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell-derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from the Dlk1-Dio3 locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically, Meg3 and other Dlk1-Dio3 locus-derived lncRNAs facilitate Ezh2/Jarid2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudal Hox genes in postmitotic MNs. Our data thus illustrate that these lncRNAs in the Dlk1-Dio3 locus, particularly Meg3, play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulating Hox genes.

scholarly journals An Inherited Lower Motor Neuron Disease of Pigs: Clinical Signs in Two Litters and Pathology of an Affected Pig

1994 ◽  
Vol 6 (1) ◽  
pp. 62-71 ◽  
Author(s):  
Donal O'Toole ◽  
James Ingram ◽  
Val Welch ◽  
Katie Bardsley ◽  
Tom Haven ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Clinical Signs ◽  
Spinal Nerve ◽  
Neuronal System ◽  
Motor Neuron Diseases ◽  
System Degeneration ◽  
Progressive Neurodegeneration ◽  
Gross Lesions

A chronic progressive neurodegeneration, called hereditary porcine neuronal system degeneration (HPNSD), was recognized in a swine herd in Devon, England. Adult pigs that were presumed carriers of the dominantly inherited trait for HPNSD were transferred from England, where a breeding colony was maintained for 9 years, to the Wyoming State Veterinary Laboratory (WSVL) for study. Two litters of affected piglets were born to 2 carrier sows at the WSVL. Clinical signs of muscular tremors, paresis, or ataxia developed at 12–59 days of age in 4 of 6 liveborn pigs. Three other pigs were stillborn. In the 4 affected livebom pigs, clinical signs progressed and included symmetrical (3 pigs) or asymmetrical (1 pig) posterior paresis, bilateral knuckling of metatarsal-phalangeal or carpal joints, poor exercise tolerance, and in 1 pig, marked hind limb hypermetria. A 34-kg gilt exhibiting clinical signs of muscular tremors and posterior paresis and clinical signs for 22 days was euthanized and examined postmortem at 83 days of age. Apart from decubitus ulcers, gross lesions were absent. Microscopically, perikaryal vacuolation and osmiophilic lipid droplets were observed in atrophic alpha motor neurons in the spinal cord. There was axonal (Wallerian) degeneration in sulcomarginal and dorsal spinocerebellar tracts. Axonal degeneration also involved ventral but not dorsal spinal nerve roots, and was present in eight peripheral nerves sampled for histopathology. Changes in skeletal muscles were consistent with denervation atrophy and were most pronounced in M. tibialis cranialis of the 6 muscles sampled. Immunohistochemical staining of spinal cord for phosphorylated and nonphosphorylated neurofilaments did not reveal abnormal patterns, unlike some well-characterized inherited motor neuron diseases in other species.

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