scholarly journals Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review

2021 ◽  
Vol 15 ◽  
Author(s):  
Amélie Poulin-Brière ◽  
Edris Rezaei ◽  
Silvia Pozzi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Passive Immunization ◽  
Therapeutic Interventions ◽  
Original Research ◽  
Motor Impairments ◽  
Research Papers ◽  
Cellular Targets ◽  
Extracellular Molecules ◽  
Present Systematic Review ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a mid-life onset neurodegenerative disease that manifests its symptomatology with motor impairments and cognitive deficits overlapping with Frontotemporal Lobar Degeneration (FTLD). The etiology of ALS remains elusive, with various mechanisms and cellular targets implicated, and no treatment can reverse or stop the progression of the pathology. Therapeutic interventions based on passive immunization are gaining attention for neurodegenerative diseases, and FDA recently approved the first antibody-based approach for Alzheimer's disease. The present systematic review of the literature aims to highlight the efforts made over the past years at developing antibody-based strategies to cure ALS. Thirty-one original research papers have been selected where the therapeutic efficacy of antibodies were investigated and described in patients and animal models of ALS. Antibody-based interventions analyzed, target both extracellular molecules implicated in the pathology and intracellular pathogenic proteins known to drive the disease, such as SOD1, TDP-43 or C9ORF72 repeats expansions. The potentials and limitations of these therapeutic interventions have been described and discussed in the present review.

scholarly journals Frontotemporal dementia and amyotrophic lateral sclerosis: Revisiting one of the first case reports with neuropathological examination

2014 ◽  
Vol 8 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Ricardo Nitrini
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Motor Neurons ◽  
Case Reports ◽  
Rare Event ◽  
Motor Impairments ◽  
Late 20Th Century ◽  
First Case ◽  
Lateral Sclerosis ◽  
Neuropathological Examination

ABSTRACT The occurrence of dementia in amyotrophic lateral sclerosis (ALS) was only widely recognized in the late 20th century. Hitherto, it was believed that dementia was a rare event due to the fortuitous association with other diseases. In 1924, Kostantin Nikolaevich Tretiakoff and Moacyr de Freitas Amorim reported a case of dementia with features of frontotemporal dementia (FTD) that preceded the motor signs of ALS. Neuropathological examination confirmed ALS and found no signs of other dementia-causing diseases. The authors hypothesized that dementia was part of ALS and recommended the search for signs of involvement of motor neurons in cases of dementia with an ill-defined clinical picture, a practice currently accepted in the investigation of cases of FTD. This was one of the first descriptions of dementia preceding the motor impairments of ALS and was published in Portuguese and French in Memórias do Hospício de Juquery.

scholarly journals Automated analysis of natural speech in amyotrophic lateral sclerosis spectrum disorders

Neurology ◽  
2020 ◽  
Vol 95 (12) ◽  
pp. e1629-e1639 ◽  
Author(s):  
Naomi Nevler ◽  
Sharon Ash ◽  
Corey McMillan ◽  
Lauren Elman ◽  
Leo McCluskey ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Primary Motor Cortex ◽  
Primary Progressive Aphasia ◽  
Automated Analysis ◽  
Pause Duration ◽  
Motor Impairments ◽  
Acoustic Measures ◽  
Cognitive Components ◽  
Spectrum Disorders ◽  
Lateral Sclerosis

ObjectiveWe implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS).MethodsWe recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS and frontotemporal degeneration [FTD]), 33 healthy controls, and neurodegenerative reference groups with behavioral variant FTD (n = 90) and nonfluent/agrammatic primary progressive aphasia (n = 23). Digitized, semistructured speech samples obtained from picture descriptions were automatically segmented with a Speech Activity Detector; continuous speech segments were pitch-tracked; and duration measures for speech and silent pause segments were extracted. Acoustic measures were calculated, including fundamental frequency (f0) range, mean speech and pause segment durations, total speech duration, and pause rate (pause count per minute of speech). Group comparisons related performance on acoustic measures to clinical scales of cognitive and motor impairments and explored MRI cortical thinning in ALS and ALS-FTD.ResultsThe f0 range was significantly impaired in ALS spectrum disorders and was related to bulbar motor disease, and regression analyses related this to cortical thickness in primary motor cortex and perisylvian regions. Impaired speech and pause duration measures were related to the degree of cognitive impairment in ALS spectrum disorders, and regressions related duration measures to bilateral frontal opercula and left anterior insula.ConclusionAutomated analyses of acoustic speech properties dissociate motor and cognitive components of speech deficits in ALS spectrum disorders.

scholarly journals A Screen to Identify Cellular Modulators of Soluble Levels of an Amyotrophic Lateral Sclerosis (ALS)–Causing Mutant SOD1

2011 ◽  
Vol 16 (9) ◽  
pp. 974-985 ◽  
Author(s):  
Balajee R. Somalinga ◽  
Gregory A. Miller ◽  
Hiba T. Malik ◽  
W. Christian Wigley ◽  
Philip J. Thomas
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
High Throughput Screening ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Protein Solubility ◽  
Global Scale ◽  
Cdna Clones ◽  
Mutant Sod1 ◽  
Cellular Targets ◽  
Lateral Sclerosis

The molecular pathology of many protein misfolding, toxic gain-of-function diseases, such as amyotrophic lateral sclerosis (ALS), is not well understood. Although protein misfolding and aggregation are common themes in these diseases, efforts to identify cellular factors that regulate this process in an unbiased fashion and on a global scale have been lacking. Using an adapted version of an extant β-gal-based protein solubility assay, an expression screen for cellular modulators of solubility of an ALS-causing mutant SOD1 was carried out in mammalian cells. Following fluorescence-activated cell sorting enrichment of a mouse spinal cord cDNA library for gene products that increased SOD1 solubility, high-throughput screening of the cDNA pools from this enriched fraction was employed to identify pools containing relevant modulators. Positive pools, containing approximately 10 cDNA clones each, were diluted and rescreened iteratively until individual clones that improved SOD1 folding/solubility were identified. Genes with profound effects in the solubility assay were selected for validation by independent biochemical assays. Six of 10 validated genes had a significant effect on SOD1 solubility and folding in a SOD1 promoter-driven β-gal assay, indicating that global screening of cellular targets using such protein solubility/folding assay is viable and can be adapted for other misfolding diseases.

scholarly journals BDNF-dependent modulation of axonal transport is selectively impaired in ALS

2021 ◽  
Author(s):  
Andrew P. Tosolini ◽  
James N. Sleigh ◽  
Sunaina Surana ◽  
Elena R. Rhymes ◽  
Stephen D. Cahalan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Axonal Transport ◽  
Neuronal Development ◽  
Therapeutic Interventions ◽  
Wild Type ◽  
Disease Pathogenesis ◽  
Sciatic Nerves ◽  
Lateral Sclerosis ◽  
Selective Impairment ◽  
Stimulation Of

AbstractAxonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments of neurons, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments are fundamental for disease pathogenesis. However, the precise mechanisms responsible for the transport deficits and whether they preferentially affect α-motor neuron (MN) subtypes remain unresolved. Here, we report that stimulation of wild-type neurons with brain-derived neurotrophic factor (BDNF) enhances trafficking of signalling endosomes specifically in fast MNs (FMNs). In early symptomatic SOD1G93A mice, FMNs display selective impairment of axonal transport and develop an insensitivity to BDNF stimulation, with pathology upregulating classical non-pro-survival receptors in muscles and sciatic nerves. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in vulnerable SOD1G93A MNs, thus identifying a new key deficit in ALS amenable for future therapeutic interventions.

Dynamic markers of altered gait rhythm in amyotrophic lateral sclerosis

2000 ◽  
Vol 88 (6) ◽  
pp. 2045-2053 ◽  
Author(s):  
Jeffrey M. Hausdorff ◽  
Apinya Lertratanakul ◽  
Merit E. Cudkowicz ◽  
Amie L. Peterson ◽  
David Kaliton ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Control ◽  
Therapeutic Interventions ◽  
Healthy Controls ◽  
Gait Dynamics ◽  
Fluctuation Dynamics ◽  
Distinct Features ◽  
Normal Controls ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.

scholarly journals Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies

2020 ◽  
Vol 9 ◽  
Author(s):  
Lauren M Gittings ◽  
Rita Sattler
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Clinical Stage ◽  
Treatment Options ◽  
Therapeutic Interventions ◽  
Current Status ◽  
Stage Of Development ◽  
Recent Advances ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by degeneration of both upper and lower motor neurons and subsequent progressive loss of muscle function. Within the last decade, significant progress has been made in the understanding of the etiology and pathobiology of the disease; however, treatment options remain limited and only two drugs, which exert a modest effect on survival, are approved for ALS treatment in the US. Therefore, the search for effective ALS therapies continues, and over 60 clinical trials are in progress for patients with ALS and other therapeutics are at the pre-clinical stage of development. Recent advances in understanding the genetics, pathology, and molecular mechanisms of ALS have led to the identification of novel targets and strategies that are being used in emerging ALS therapeutic interventions. Here, we review the current status and mechanisms of action of a selection of emerging ALS therapies in pre-clinical or early clinical development, including gene therapy, immunotherapy, and strategies that target neuroinflammation, phase separation, and protein clearance.

Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis

2014 ◽  
Vol 56 ◽  
pp. 149-165 ◽  
Author(s):  
Helen R. Broom ◽  
Jessica A.O. Rumfeldt ◽  
Elizabeth M. Meiering
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Structural Features ◽  
Neuron Death ◽  
Cellular Targets ◽  
Copper Zinc Superoxide Dismutase ◽  
Multiple Species ◽  
Lateral Sclerosis

ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative syndrome characterized by progressive paralysis and motor neuron death. Although the pathological mechanisms that cause ALS remain unclear, accumulating evidence supports that ALS is a protein misfolding disorder. Mutations in Cu,Zn-SOD1 (copper/zinc superoxide dismutase 1) are a common cause of familial ALS. They have complex effects on different forms of SOD1, but generally destabilize the protein and enhance various modes of misfolding and aggregation. In addition, there is some evidence that destabilized covalently modified wild-type SOD1 may be involved in disease. Among the multitude of misfolded/aggregated species observed for SOD1, multiple species may impair various cellular components at different disease stages. Newly developed antibodies that recognize different structural features of SOD1 represent a powerful tool for further unravelling the roles of different SOD1 structures in disease. Evidence for similar cellular targets of misfolded/aggregated proteins, loss of cellular proteostasis and cell–cell transmission of aggregates point to common pathological mechanisms between ALS and other misfolding diseases, such as Alzheimer's, Parkinson's and prion diseases, as well as serpinopathies. The recent progress in understanding the molecular basis for these devastating diseases provides numerous avenues for developing urgently needed therapeutics.

scholarly journals Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

2015 ◽  
Vol 113 (3) ◽  
pp. 614-619 ◽  
Author(s):  
Elizabeth A. Proctor ◽  
Lanette Fee ◽  
Yazhong Tao ◽  
Rachel L. Redler ◽  
James M. Fay ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Molecular Etiology ◽  
Superoxide Dismutase Gene ◽  
Lateral Sclerosis

Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies.

Sign in / Sign up

Export Citation Format

Share Document