Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques

Bos, Mehdi van den; Geevasinga, Nimeshan; Higashihara, Mana; Menon, Parvathi; Vucic, Steve

doi:10.3390/ijms20112818

Cited by 100 publications

(65 citation statements)

References 135 publications

(231 reference statements)

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“…Where ALS disease begins has remained argumentative. One of the hypotheses is "dying-back", in which ALS begins within the lower motor neurons (LMN) and then the pathology spreads from LMN to the upper motor neurons (UMN) [15,17,66]. Notably, in our study, while there was already 30% loss of motor neurons in the lumbar region of the spinal cord of N390D/+ male mice at the age of 6 months (Fig.…”

Section: Age-dependent Mislocalization Of Tdp-43 and Ptdp-43 Accumulmentioning

confidence: 54%

A robust TDP-43 knock-in mouse model of ALS

Huang

Lee

et al. 2020

acta neuropathol commun

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Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS-TDP.

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Section: Age-dependent Mislocalization Of Tdp-43 and Ptdp-43 Accumulmentioning

confidence: 54%

A robust TDP-43 knock-in mouse model of ALS

Huang

Lee

et al. 2020

acta neuropathol commun

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“…In clinics, ALS diagnosis relies on evidence of combined degeneration of UMN in the motor cortex, and LMN in the brain stem and spinal cord. This dual impairment nourished a still unresolved debate regarding the potential origin of the neurodegeneration: cortical versus spinal (reviewed in [ 31 ]). For Charcot, the lateral sclerosis, i.e., the degeneration of the corticospinal tracts that contain the axons of the UMN and that run laterally in human, was amyotrophic, i.e., responsible for the degeneration of the LMN and the muscular denervation [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Upper and Lower Motor Neuron Degenerations Are Somatotopically Related and Temporally Ordered in the Sod1 Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2021

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Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease arising from the combined degeneration of upper motor neurons (UMN) in the motor cortex, and lower motor neurons (LMN) in the brainstem and spinal cord. This dual impairment raises two major questions: (i) are the degenerations of these two neuronal populations somatotopically related? and if yes (ii), where does neurodegeneration start? If studies carried out on ALS patients clearly demonstrated the somatotopic relationship between UMN and LMN degenerations, their temporal relationship remained an unanswered question. In the present study, we took advantage of the well-described Sod1G86R model of ALS to interrogate the somatotopic and temporal relationships between UMN and LMN degenerations in ALS. Using retrograde labelling from the cervical or lumbar spinal cord of Sod1G86R mice and controls to identify UMN, along with electrophysiology and histology to assess LMN degeneration, we applied rigorous sampling, counting, and statistical analyses, and show that UMN and LMN degenerations are somatotopically related and that UMN depletion precedes LMN degeneration. Together, the data indicate that UMN degeneration is a particularly early and thus relevant event in ALS, in accordance with a possible cortical origin of the disease, and emphasize the need to further elucidate the molecular mechanisms behind UMN degeneration, towards new therapeutic avenues.

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“…Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by progressive degeneration of motor neurons in the spinal cord and the motor cortex, resulting in global muscle weakness, paralysis, and ultimately death due to respiratory dysfunction [ 23 , 24 ]. Currently, the only FDA-approved treatments for this neurodegenerative disease (riluzole and edaravone) have limited effects [ 25 ].…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Fingolimod as a Treatment in Neurologic Disorders Beyond Multiple Sclerosis

et al. 2020

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Fingolimod is an approved treatment for relapsing–remitting multiple sclerosis (MS), and its properties in different pathways have raised interest in therapy research for other neurodegenerative diseases. Fingolimod is an agonist of sphingosine-1-phosphate (S1P) receptors. Its main pharmacologic effect is immunomodulation by lymphocyte homing, thereby reducing the numbers of T and B cells in circulation. Because of the ubiquitous expression of S1P receptors, other effects have also been described. Here, we review preclinical experiments evaluating the effects of treatment with fingolimod in neurodegenerative diseases other than MS, such as Alzheimer’s disease or epilepsy. Fingolimod has shown neuroprotective effects in different animal models of neurodegenerative diseases, summarized here, correlating with increased brain-derived neurotrophic factor and improved disease phenotype (cognition and/or motor abilities). As expected, treatment also induced reductions in different neuroinflammatory markers because of not only inhibition of lymphocytes but also direct effects on astrocytes and microglia. Furthermore, fingolimod treatment exhibited additional effects for specific neurodegenerative disorders, such as reduction of amyloid-β production, and antiepileptogenic properties. The neuroprotective effects exerted by fingolimod in these preclinical studies are reviewed and support the translation of fingolimod into clinical trials as treatment in neurodegenerative diseases beyond neuroinflammatory conditions (MS).

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Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques

Cited by 100 publications

References 135 publications

A robust TDP-43 knock-in mouse model of ALS

A robust TDP-43 knock-in mouse model of ALS

Upper and Lower Motor Neuron Degenerations Are Somatotopically Related and Temporally Ordered in the Sod1 Mouse Model of Amyotrophic Lateral Sclerosis

Fingolimod as a Treatment in Neurologic Disorders Beyond Multiple Sclerosis

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