scholarly journals A new zebrafish model produced by TILLING of SOD1-related amyotrophic lateral sclerosis replicates key features of the disease and represents a tool for in vivo therapeutic screening

2013 ◽  
Vol 7 (1) ◽  
pp. 73-81 ◽  
Author(s):  
M. M. J. Da Costa ◽  
C. E. Allen ◽  
A. Higginbottom ◽  
T. Ramesh ◽  
P. J. Shaw ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Zebrafish Model ◽  
Key Features ◽  
Lateral Sclerosis

scholarly journals Where and Why Modeling Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 22 (8) ◽  
pp. 3977
Author(s):  
Francesco Liguori ◽  
Susanna Amadio ◽  
Cinzia Volonté
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Comparative Analysis ◽  
Clinical Presentation ◽  
In Vivo Models ◽  
Comprehensive Review ◽  
Common Features ◽  
Neuroinflammatory Disease ◽  
Multicellular Organisms ◽  
Lateral Sclerosis

Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals In Vivo Validation of Bimolecular Fluorescence Complementation (BiFC) to Investigate Aggregate Formation in Amyotrophic Lateral Sclerosis (ALS)

2020 ◽  
Author(s):  
Emily K Don ◽  
Alina Maschirow ◽  
Rowan A W Radford ◽  
Natalie M Scherer ◽  
Andres Vidal-Itriago ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Onset ◽  
Bimolecular Fluorescence Complementation ◽  
Aggregate Formation ◽  
Reporter Protein ◽  
Fluorescent Reporter ◽  
Lateral Sclerosis ◽  
Fluorescence Complementation ◽  
Bimolecular Fluorescence

AbstractAmyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND) that is characterized by the progressive loss of motor neurons within the spinal cord, brainstem and motor cortex. Although ALS clinically manifests as a heterogeneous disease, with varying disease onset and survival, a unifying feature is the presence of ubiquitinated cytoplasmic protein inclusion aggregates containing TDP-43. However, the precise mechanisms linking protein inclusions and aggregation to neuronal loss are currently poorly understood.Bimolecular Fluorescence Complementation (BiFC) takes advantage the association of fluorophore fragments (non-fluorescent on their own) that are attached to an aggregation prone protein of interest. Interaction of the proteins of interest allows for the fluorescent reporter protein to fold into its native state and emit a fluorescent signal. Here, we combined the power of BiFC with the advantages of the zebrafish system to validate, optimize and visualize of the formation of ALS-linked aggregates in real time in a vertebrate model. We further provide in vivo validation of the selectivity of this technique and demonstrate reduced spontaneous self-assembly of the non-fluorescent fragments in vivo by introducing a fluorophore mutation. Additionally, we report preliminary findings on the dynamic aggregation of the ALS-linked hallmark proteins Fus and TDP-43 in their corresponding nuclear and cytoplasmic compartments using BiFC.Overall, our data demonstrates the suitability of this BiFC approach to study and characterize ALS-linked aggregate formation in vivo. Importantly, the same principle can be applied in the context of other neurodegenerative diseases and has therefore critical implications to advance our understanding of pathologies that underlie aberrant protein aggregation.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

Toward in vivo determination of peripheral nervous system immune activity in amyotrophic lateral sclerosis

2019 ◽  
Vol 59 (5) ◽  
pp. 567-576 ◽  
Author(s):  
Stefanie Schreiber ◽  
Frank Schreiber ◽  
Cornelia Garz ◽  
Grazyna Debska‐Vielhaber ◽  
Anne Assmann ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Immune Activity ◽  
Lateral Sclerosis

scholarly journals Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiaki Furukawa
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Wild Type ◽  
Sporadic Als ◽  
Familial Form ◽  
Recent Developments ◽  
Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

A novel alternative splicing event rescues the mutant tardbp phenotype in a zebrafish model of TDP-43 related Amyotrophic Lateral Sclerosis (ALS) (P03.180)

Neurology ◽  
2012 ◽  
Vol 78 (Meeting Abstracts 1) ◽  
pp. P03.180-P03.180
Author(s):  
C. Hewamadduma ◽  
A. Grierson ◽  
C. Moens ◽  
L. Pan ◽  
T. Ma ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Alternative Splicing ◽  
Zebrafish Model ◽  
Lateral Sclerosis
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