scholarly journals Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

2016 ◽  
Vol 113 (47) ◽  
pp. E7580-E7589 ◽  
Author(s):  
Nhat T. T. Le ◽  
Lydia Chang ◽  
Irina Kovlyagina ◽  
Polymnia Georgiou ◽  
Nathaniel Safren ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Hippocampal Neurons ◽  
Missense Mutations ◽  
Spinal Motor Neurons ◽  
Stage Disease ◽  
End Stage ◽  
Brain And Spinal Cord ◽  
The Brain

Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS–FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS–FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin+ inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS–FTD pathogenesis and for investigating therapeutic strategies to halt disease.

scholarly journals Experimental Motor Neuron Disease Induced in Mice with Long-Term Repeated Intraperitoneal Injections of Serum from ALS Patients

2019 ◽  
Vol 20 (10) ◽  
pp. 2573 ◽  
Author(s):  
Izabella Obál ◽  
Bernát Nógrádi ◽  
Valéria Meszlényi ◽  
Roland Patai ◽  
Gerda Ricken ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Intracellular Calcium ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Isometric Force ◽  
Motor Nerve ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Gradual Loss ◽  
Als Patients

In an earlier study, signs of commencing degeneration of spinal motor neurons were induced in mice with short-term intraperitoneal injections of immunoglobulin G (IgG) taken from patients with amyotrophic lateral sclerosis (ALS). Since in that study, neither weakness nor loss of motor neurons was noted, to test whether the ALS IgG in this paradigm has the potential to evoke relentless degeneration of motor neurons, treatment with repeated injections over a longer period was carried out. Mice were systematically injected intraperitoneally with serum taken from ALS patients over a 75-day period. At selected time points, the isometric force of the limbs, number of spinal motor neurons and their intracellular calcium levels were determined. Furthermore, markers of glial activation and the motoneuronal uptake of human IgG were monitored. During this period, gliosis and progressive motoneuronal degeneration developed, which led to gradual loss of spinal motor neurons, more than 40% at day 21, along with decreasing muscle strength in the limbs. The inclusion-like accumulation of IgG appeared in the perikarya with the increase of intracellular calcium in the cell bodies and motor nerve terminals. Our results demonstrate that ALS serum can transfer motor neuron disease to mice.

scholarly journals ALS-Like Disorder in Three HIV-Positive Patients: Case Series

2021 ◽  
pp. 59-64
Author(s):  
Zachary Aaron Satin ◽  
Elham Bayat
Keyword(s):  
Antiretroviral Therapy ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Case Series ◽  
Retrospective Chart Review ◽  
Effective Control ◽  
Hiv Positive ◽  
Disease Course ◽  
Retroviral Infection

There appears to be a relationship between retroviruses such as HIV and the development of an ALS-like syndrome. Few cases have been reported; however, there exists evidence of a higher frequency of motor neuron disease in HIV-infected patients, as well as potential slowing and reversibility of disease course with combination antiretroviral therapy. We conducted a retrospective chart review of patients presenting to the George Washington University ALS Clinic from September 2006 to June 2018 to identify patients with HIV receiving HAART who were subsequently diagnosed with ALS or an ALS-like disorder. Our goals were to describe our patients’ disease course and compare them to general characteristics of ALS. We report three cases of HIV-positive individuals, all male, who were subsequently diagnosed with ALS. Each presented with symptoms of limb onset ALS with involvement of upper and lower motor neurons and whose disease originated at the cervical level. All three had been diagnosed with HIV prior to presentation and were presumably compliant with antiretroviral therapy throughout. Our patients demonstrated effective control of their HIV infection. Each experienced relatively slow progression of motor impairment compared to general ALS characteristics. Our study offers a distinct profile of HIV-positive patients compliant with HAART subsequently diagnosed with an ALS-like disorder. Further study should aim to uncover pathophysiological similarities between motor neuron disease both in the presence and absence of retroviral infection and to develop effective medical therapy for each.

scholarly journals Müllerian inhibiting substance contributes to sex-linked biases in the brain and behavior

2009 ◽  
Vol 106 (17) ◽  
pp. 7203-7208 ◽  
Author(s):  
Pei-Yu Wang ◽  
Anna Protheroe ◽  
Andrew N. Clarkson ◽  
Floriane Imhoff ◽  
Kyoko Koishi ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Reproductive Tract ◽  
Behavioral Traits ◽  
Spinal Motor Neurons ◽  
Müllerian Inhibiting Substance ◽  
Males And Females ◽  
Brain And Behavior ◽  
And Behavior ◽  
The Brain ◽  
Mullerian Inhibiting Substance

Many behavioral traits and most brain disorders are common to males and females but are more evident in one sex than the other. The control of these subtle sex-linked biases is largely unstudied and has been presumed to mirror that of the highly dimorphic reproductive nuclei. Sexual dimorphism in the reproductive tract is a product of Müllerian inhibiting substance (MIS), as well as the sex steroids. Males with a genetic deficiency in MIS signaling are sexually males, leading to the presumption that MIS is not a neural regulator. We challenge this presumption by reporting that most immature neurons in mice express the MIS-specific receptor (MISRII) and that male Mis−/− and Misrii−/− mice exhibit subtle feminization of their spinal motor neurons and of their exploratory behavior. Consequently, MIS may be a broad regulator of the subtle sex-linked biases in the nervous system.

scholarly journals Amyotrophic lateral sclerosis: one or multiple causes?

2011 ◽  
Vol 3 (1) ◽  
pp. 4 ◽  
Author(s):  
Aline Furtado Bastos ◽  
Marco Orsini ◽  
Dionis Machado ◽  
Mariana Pimentel Mello ◽  
Sergio Nader ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Viral Infections ◽  
Vigorous Physical Activity ◽  
Disease Etiology ◽  
New Research ◽  
Lateral Sclerosis

The Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease in the adulthood, and it is characterized by rapid and progressive compromise of the upper and lower motor neurons. The majority of the cases of ALS are classified as sporadic and, until now, a specific cause for these cases still is unknown. To present the different hypotheses on the etiology of ALS. It was carried out a search in the databases: Bireme, Scielo and Pubmed, in the period of 1987 to 2011, using the following keywords: Amyotrophic lateral sclerosis, motor neuron disease, etiology, causes and epidemiology and its similar in Portuguese and Spanish. It did not have consensus as regards the etiology of ALS. Researches demonstrates evidences as regards intoxication by heavy metals, environmental and occupational causes, genetic mutations (superoxide dismutase 1), certain viral infections and the accomplishment of vigorous physical activity for the development of the disease. There is still no consensus regarding the involved factors in the etiology of ALS. In this way, new research about these etiologies are necessary, for a better approach of the patients, promoting preventive programs for the disease and improving the quality of life of the patients.

scholarly journals Multidisciplinary Interventions in Motor Neuron Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
U. E. Williams ◽  
E. E. Philip-Ephraim ◽  
S. K. Oparah
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Cellular Processes ◽  
Team Care ◽  
Respiratory Management ◽  
Care Approach ◽  
Management Of Dysphagia

Motor neuron disease is a neurodegenerative disease characterized by loss of upper motor neuron in the motor cortex and lower motor neurons in the brain stem and spinal cord. Death occurs 2–4 years after the onset of the disease. A complex interplay of cellular processes such as mitochondrial dysfunction, oxidative stress, excitotoxicity, and impaired axonal transport are proposed pathogenetic processes underlying neuronal cell loss. Currently evidence exists for the use of riluzole as a disease modifying drug; multidisciplinary team care approach to patient management; noninvasive ventilation for respiratory management; botulinum toxin B for sialorrhoea treatment; palliative care throughout the course of the disease; and Modafinil use for fatigue treatment. Further research is needed in management of dysphagia, bronchial secretion, pseudobulbar affect, spasticity, cramps, insomnia, cognitive impairment, and communication in motor neuron disease.

scholarly journals Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis

2016 ◽  
Vol 74 (10) ◽  
pp. 849-854
Author(s):  
Paulo Victor Sgobbi de Souza ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
Flávio Moura Rezende Filho ◽  
Acary Souza Bulle Oliveira
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Glial Cell ◽  
Glial Cells ◽  
Motor Neurons ◽  
Cell Interaction ◽  
Cell Functions ◽  
Glial Cell Interactions ◽  
Lateral Sclerosis

ABSTRACT Motor neuron disease is one of the major groups of neurodegenerative diseases, mainly represented by amyotrophic lateral sclerosis. Despite wide genetic and biochemical data regarding its pathophysiological mechanisms, motor neuron disease develops under a complex network of mechanisms not restricted to the unique functions of the alpha motor neurons but which actually involve diverse functions of glial cell interaction. This review aims to expose some of the leading roles of glial cells in the physiological mechanisms of neuron-glial cell interactions and the mechanisms related to motor neuron survival linked to glial cell functions.

scholarly journals Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Tai-Heng Chen ◽  
Jun-An Chen
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Cell Types ◽  
Spinal Motor Neurons ◽  
Potential Applications ◽  
The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

scholarly journals Pathologic Thr175 tau phosphorylation in CTE and CTE with ALS

Neurology ◽  
2018 ◽  
Vol 90 (5) ◽  
pp. e380-e387 ◽  
Author(s):  
Alexander J. Moszczynski ◽  
Wendy Strong ◽  
Kathy Xu ◽  
Ann McKee ◽  
Arthur Brown ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Hippocampal Neurons ◽  
Glycogen Synthase ◽  
Chronic Traumatic Encephalopathy ◽  
Spinal Cord Tissue ◽  
Tau Pathology ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Pathologic Features ◽  
Lateral Sclerosis

ObjectiveTo investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr175 (pThr175 tau) and Thr231 (pThr231 tau), and glycogen synthase kinase–3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI).MethodsTau isoform expression was assayed by western blot in 6 stage III CTE cases. We also used immunohistochemistry to analyze 5 cases each of CTE, CTE-ALS, and 5 controls for expression of activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau within spinal cord tissue and hippocampus. Using a rat model of moderate TBI, we assessed tau pathology and phospho-GSK3β expression at 3 months postinjury.ResultsCTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau protein expression was observed in hippocampal neurons and spinal motor neurons. We observed tau neuronal pathology (fibrillar inclusions and axonal damage) and increased levels of pThr175 tau and activated GSK3β in moderate TBI rats.ConclusionsPathologic phosphorylation of tau at Thr175 and Thr231 and activation of GSK3β are features of the tauopathy of CTE and CTE-ALS. These features can be replicated in an animal model of moderate TBI.

scholarly journals Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Alison M. Hixon ◽  
Penny Clarke ◽  
Kenneth L. Tyler
Keyword(s):  
Sialic Acid ◽  
Motor Neuron ◽  
Axonal Transport ◽  
Motor Neurons ◽  
The United States ◽  
Retrograde Axonal Transport ◽  
Spinal Motor Neurons ◽  
Acute Flaccid Myelitis ◽  
Spinal Motor ◽  
Enterovirus D68

ABSTRACTEnterovirus D68 (EV-D68) is an emerging virus that has been identified as a cause of recent outbreaks of acute flaccid myelitis (AFM), a poliomyelitis-like spinal cord syndrome that can result in permanent paralysis and disability. In experimental mouse models, EV-D68 spreads to, infects, and kills spinal motor neurons following infection by various routes of inoculation. The topography of virus-induced motor neuron loss correlates with the pattern of paralysis. The mechanism(s) by which EV-D68 spreads to target motor neurons remains unclear. We sought to determine the capacity of EV-D68 to spread by the neuronal route and to determine the role of known EV-D68 receptors, sialic acid and intracellular adhesion molecule 5 (ICAM-5), in neuronal infection. To do this, we utilized a microfluidic chamber culture system in which human induced pluripotent stem cell (iPSC) motor neuron cell bodies and axons can be compartmentalized for independent experimental manipulation. We found that EV-D68 can infect motor neurons via their distal axons and spread by retrograde axonal transport to the neuronal cell bodies. Virus was not released from the axons via anterograde axonal transport after infection of the cell bodies. Prototypic strains of EV-D68 depended on sialic acid for axonal infection and transport, while contemporary circulating strains isolated during the 2014 EV-D68 outbreak did not. The pattern of infection did not correspond with the ICAM-5 distribution and expression in either human tissue, the mouse model, or the iPSC motor neurons.IMPORTANCEEnterovirus D68 (EV-D68) infections are on the rise worldwide. Since 2014, the United States has experienced biennial spikes in EV-D68-associated acute flaccid myelitis (AFM) that have left hundreds of children paralyzed. Much remains to be learned about the pathogenesis of EV-D68 in the central nervous system (CNS). Herein we investigated the mechanisms of EV-D68 CNS invasion through neuronal pathways. A better understanding of EV-D68 infection in experimental models may allow for better prevention and treatment strategies of EV-D68 CNS disease.

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