A5005231504- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Prion Diseases and Protein Misfolding
- Cancer-related gene regulation
- biodegradable polymer synthesis and properties
- Pesticide Exposure and Toxicity
- Endoplasmic Reticulum Stress and Disease
- Muscle activation and electromyography studies
- Pluripotent Stem Cells Research
- Antiplatelet Therapy and Cardiovascular Diseases
- RNA Research and Splicing
- Parasites and Host Interactions
- Synthetic Organic Chemistry Methods
- Attention Deficit Hyperactivity Disorder
- Epigenetics and DNA Methylation
- Dysphagia Assessment and Management
- Cancer Cells and Metastasis
- Coronary Interventions and Diagnostics
- Psychology and Mental Health
- Conducting polymers and applications
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Cholinesterase and Neurodegenerative Diseases
- Nerve injury and regeneration
- Alzheimer's disease research and treatments
Amyotrophic Lateral Sclerosis Therapy Development Institute
2014-2024
Malcom Randall VA Medical Center
2004
Florida College
2004
University of Florida
2004
Identification of SOD1 as the mutated protein in a significant subset familial amyotrophic lateral sclerosis (FALS) cases has led to generation transgenic rodent models autosomal dominant FALS. Mice carrying 23 copies human SOD1G93A transgene are considered standard model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing agents that extend lifespan this mouse. However, no agent besides riluzole shown corresponding clinical efficacy.We used...
The development of therapeutics for ALS/MND is largely based on work in experimental animals carrying human SOD mutations. However, translation apparent therapeutic successes from vivo to the disease has proven difficult and a considerable amount financial resources been apparently wasted. Standard operating procedures (SOPs) preclinical animal research are urgently required. Such SOPs will help establish translational other neurological diseases within next few years. To identify challenges...
Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment function. Promising drug development efforts have accelerated amyotrophic sclerosis, but are constrained by a lack objective, sensitive, accessible outcome measures. Here we investigate the use wearable sensors, worn on four limbs at home during natural behavior, to quantify function disease progression 376 individuals with sclerosis. We an analysis approach that...
The SOD1-G93A transgenic mouse is the most widely used animal model of amyotrophic lateral sclerosis (ALS). At ALS TDI we developed a phenotypic screening protocol, demonstrated in video herein, which reliably assesses neuromuscular function mice quick manner. This protocol encompasses simple neurological scoring system (NeuroScore) designed to assess hindlimb function. NeuroScore focused on because deficits are earliest reported sign disease mice. by provides an unbiased assessment onset...
ABSTRACT Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much known about effects of ALS on neurons and glial cells, little its effect proprioceptive sensory neurons. This study examines in mice harboring mutations associated with ALS, SOD1 G93A TDP43 A315T transgenic mice. In both lines, we found fewer containing fluorescently tagged cholera toxin their soma five days after injecting this retrograde tracer into tibialis...
Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 cause familial amyotrophic lateral sclerosis (FALS). However, implications wild-type sporadic forms ALS (SALS) remain unclear. By screening human memory B cells from a large cohort healthy elderly subjects, we generated recombinant monoclonal antibody (α-miSOD1) that selectively bound misfolded SOD1, but not physiological dimers. On postmortem spinal cord sections 121 patients with ALS,...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to neuron degeneration in ALS are unclear. However, there evidence for involvement endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) ALS, notably mutant SOD1 mediated models ALS. Stress induced phosphorylation eIF2 alpha subunit eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates UPR. Guanabenz centrally...
Abstract Non-natively folded variants of superoxide dismutase 1 (SOD1) are thought to contribute the pathogenesis familial amyotrophic lateral sclerosis (ALS), however relative toxicities these controversial. Here, we aimed decipher relationships between different SOD1 (aggregated, soluble misfolded, total) and clinical presentation ALS in G93A mouse. Using a multi-approach strategy, found that CNS regions least affected by disease had most aggregated SOD1. We also levels spinal cord were...
A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion C9ORF72 gene and its relevance frontotemporal dementia (FTD) amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this was to connect basic scientists, clinical researchers, drug developers, individuals affected by C9ORF72-FTD/ALS evaluate how collaborative efforts across FTD-ALS disease spectrum might break down existing silos. Presentations discussions covered recent...
In any animal model of human disease a positive control therapy that demonstrates efficacy in both the and can validate application to discovery new therapeutics. Such has recently been reported by Fornai et al. using chronic lithium carbonate treatment showing therapeutic high-copy SOD1G93A mouse familial amyotrophic lateral sclerosis (ALS), ALS patients.Seeking verify this therapy, we tested dosing sibling-matched, gender balanced, investigator-blinded trial (average 23 copies) (n =...
Amyotrophic Lateral Sclerosis (ALS) disease severity is usually measured using the subjective, questionnaire-based revised ALS Functional Rating Scale (ALSFRS-R). Objective measures of would be powerful tools for evaluating real-world drug effectiveness, efficacy in clinical trials, and identifying participants cohort studies. We developed a machine learning (ML) based objective measure on voice samples accelerometer measurements from four-year longitudinal dataset. 584 people living with...
Digital health technologies (DHTs) can quantify movements in daily routines but rely heavily on participant adherence over prolonged wear times. Here we analyze accelerometry data from wrist-worn devices during short episodes of prescribed exercises (PEs) performed by 329 individuals living with amyotrophic lateral sclerosis (ALS) a longitudinal study. We developed an automated and interpretable signal processing method to estimate upper limb movement counts, duration, intensity, similarity...
Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement ALS.Randomization 2:1 (fingolimod:placebo). Treatment duration 4 weeks. Primary outcomes were safety tolerability. Secondary included lymphocytes whole-blood gene expression.Thirty participants randomized; 28 administered a...
A copper chelator known as diacetylbis(N(4)-methylthiosemicarbazonato) II (CuATSM), has been reported to be efficacious in multiple transgenic SOD1 models of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting motor neurons. Here we report that also observed CuATSM efficacy on disease onset and progression standardized litter-matched gender-balanced study using B6SJL-SOD1G93A/1Gur mice. We improved survival trends with treatment. In addition, lack by...
Intronic repeat expansions in the
Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Histone deacetylase (HDAC) inhibitors have neuroprotective effects potentially useful for treatment of diseases including ALS; however, molecular mechanisms underlying their potential efficacy not well understood. Here we report protein acetylation urea-soluble proteins differently regulated post-mortem ALS Two-dimensional electrophoresis...
Abstract There is increased recognition that sensory neurons located in dorsal root ganglia (DRG) are affected amyotrophic lateral sclerosis (ALS). However, it remains unknown whether ALS-inducing factors, other than mutant superoxide dismutase 1 (SOD1 G93A ), directly affect neurons. Here, we examined the effect of TAR DNA-binding protein (TDP43 A315T ) on culture and vivo . In parallel, reevaluated expressing SOD1 We found cultured harboring either TDP43 or grow neurites at a slower rate...
Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy high-copy B6-SJL-SOD1G93A/Gur1 mice, 2) high-content neuronal primary rat cortical neurons transfected wild-type TDP43 or mutant TDP43. both cases, exposed...
Repeat expansion mutations in the C9ORF72 gene are most common genetic cause of amyotrophic lateral sclerosis (ALS) and (FTD). Repeat-associated non-AUG translation this produces dipeptide repeat proteins (DRPs). The arginine containing DRPs, polyGR polyPR, consistently reported to be toxic. Here we demonstrated that small molecule inhibition Type I protein methyltransferases protects against polyPR toxicity. Furthermore, our findings suggest asymmetric dimethylation by PRMTs play important...
A repeat expansion mutation in the C9orf72 gene is most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this study, using multiple cell-based assay systems, we reveal both increased dipeptide protein (DRP) toxicity primary neurons differentiated neuronal cell lines. Using flow cytometry confocal laser scanning microscopy cells treated with fluorescein isothiocyanate (FITC)-labeled DRPs, confirm that poly-glycine-arginine (GR)...
Hexanucleotide repeat expansion (G4C2 n ) mutations in the gene C9ORF72 account for approximately 30% of familial cases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well 7% sporadic ALS. G4C2 are known to result production five species dipeptide proteins (DRPs) through non-canonical translation processes. Arginine-enriched proteins, glycine-arginine (polyGR), proline-arginine (polyPR) have been demonstrated be cytotoxic deleterious multiple experimental systems....
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much known about effects of ALS on neurons and glial cells, little its effect proprioceptive sensory neurons. This study examines in mice harboring mutations associated with ALS, SOD1G93A TDP43A315T transgenic mice. In both lines, we found fewer containing fluorescently tagged cholera toxin their soma five days after injecting this retrograde tracer into tibialis anterior...