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Journal of Cerebral Blood Flow and... May 2023There is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral... (Review)
Review
There is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Since impairment of the blood-central nervous system barrier (BCNSB) occurs during the pre-symptomatic stages of ALS, the mechanisms underlying this pathology are likely also involved in the ALS disease process. In this review, we explore how drivers of ALS disease, particularly mitochondrial dysfunction, astrocyte pathology and neuroinflammation, may contribute to BCNSB impairment. Mitochondria are highly abundant in BCNSB tissue and mitochondrial dysfunction in ALS contributes to motor neuron death. Likewise, astrocytes adopt key physical, transport and metabolic functions at the barrier, many of which are impaired in ALS. Astrocytes also show raised expression of inflammatory markers in ALS and ablating ALS-causing transgenes in astrocytes slows disease progression. In addition, key drivers of neuroinflammation, including TAR DNA-binding protein 43 (TDP-43) pathology, matrix metalloproteinase activation and systemic inflammation, affect BCNSB integrity in ALS. Finally, we discuss the translational implications of BCNSB dysfunction in ALS, including the development of biomarkers for disease onset and progression, approaches aimed at restoring BCNSB integrity and modelling of the neurogliovascular system.
Topics: Animals; Humans; Amyotrophic Lateral Sclerosis; Neuroinflammatory Diseases; Motor Neurons; Spinal Cord; Astrocytes; Disease Models, Animal
PubMed: 36704819
DOI: 10.1177/0271678X231153281 -
Neurological Sciences : Official... Feb 2021The present review represents an update about the knowledge of the possible role of Cadmium (Cd) in amyotrophic lateral sclerosis (ALS) initiation and its progression.... (Review)
Review
The present review represents an update about the knowledge of the possible role of Cadmium (Cd) in amyotrophic lateral sclerosis (ALS) initiation and its progression. ALS is a neurodegenerative disease that occurs in adulthood; its etiology is unknown and leads to death within a few years from its appearance. Among the various possible causes that can favor the development of the disease, heavy metals cannot be excluded. Cadmium is a heavy metal that does not play a biological role, but its neurotoxicity is well known. Numerous in vitro studies on cell and animal models confirm the toxicity of the metal on the nervous system, but these data are not accompanied by an epidemiological evidence, and, thus, an unclear correlation between Cd and the onset of the disease can be pointed out. On the other hand, a possible multifactorial and synergic mechanism in which Cd may have a role can explain the ALS onset. More efforts in new clinical, biochemical, and epidemiological studies are necessary to better elucidate the involvement of Cd in this lethal disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cadmium; Neurodegenerative Diseases
PubMed: 33280067
DOI: 10.1007/s10072-020-04957-7 -
Current Neurology and Neuroscience... May 2020In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge... (Review)
Review
PURPOSE OF REVIEW
In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge on causes, pathophysiology, and treatment of sleep disturbances in ALS.
RECENT FINDINGS
Motor neuron degeneration and muscle weakness may lead to muscle cramps, pain, spasticity, immobilization, restless legs, sleep-disordered breathing, and difficulties to clear secretions. Furthermore, existential fears and depression may promote insomnia. Sleep-disordered breathing, and nocturnal hypoventilation in particular, requires ventilatory support which meaningfully prolongs survival and improves health-related quality of life albeit respiratory failure is inevitable. Early indication for non-invasive ventilation can be achieved by inclusion of capnometry in diagnostic sleep studies. Sleep disruption is extremely common in ALS and may arise from different etiologies. The absence of causative therapeutic options for ALS underlines the importance of symptomatic and palliative treatment strategies that acknowledge sleep-related complaints.
Topics: Amyotrophic Lateral Sclerosis; Humans; Polysomnography; Quality of Life; Respiratory Insufficiency; Sleep
PubMed: 32462331
DOI: 10.1007/s11910-020-01047-1 -
Arquivos de Neuro-psiquiatria Jul 2022
Topics: Amyotrophic Lateral Sclerosis; Brazil; Humans
PubMed: 36254436
DOI: 10.1055/s-0042-1755281 -
Cells Mar 2023Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and ultimately death. The mechanisms underlying ALS pathogenesis have not yet been fully elucidated, and ALS cannot be treated effectively. Most studies have applied animal or single-gene intervention cell lines as ALS disease models, but they cannot accurately reflect the pathological characteristics of ALS. Induced pluripotent stem cells (iPSCs) can be reprogrammed from somatic cells, possessing the ability to self-renew and differentiate into a variety of cells. iPSCs can be obtained from ALS patients with different genotypes and phenotypes, and the genetic background of the donor cells remains unchanged during reprogramming. iPSCs can differentiate into neurons and glial cells related to ALS. Therefore, iPSCs provide an excellent method to evaluate the impact of diseases on ALS patients. Moreover, patient-derived iPSCs are obtained from their own somatic cells, avoiding ethical concerns and posing only a low risk of immune rejection. The iPSC technology creates new hope for ALS treatment. Here, we review recent studies on iPSCs and their applications in disease modeling, drug screening and cell therapy in ALS, with a particular focus on the potential for ALS treatment.
Topics: Animals; Amyotrophic Lateral Sclerosis; Induced Pluripotent Stem Cells; Neurodegenerative Diseases; Neurons; Cell- and Tissue-Based Therapy
PubMed: 36980310
DOI: 10.3390/cells12060971 -
Cells Nov 2020Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more... (Review)
Review
Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular "clearance" system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Autophagy; Caloric Restriction; Genetic Predisposition to Disease; Humans; Models, Biological; Molecular Targeted Therapy
PubMed: 33158177
DOI: 10.3390/cells9112413 -
International Journal of Molecular... Mar 2023Transactive response element DNA/RNA-binding protein 43 kDa (TDP-43) is the causative protein of amyotrophic lateral sclerosis (ALS); several ALS-associated mutants of...
Transactive response element DNA/RNA-binding protein 43 kDa (TDP-43) is the causative protein of amyotrophic lateral sclerosis (ALS); several ALS-associated mutants of TDP-43 have been identified. TDP-43 has several domains: an N-terminal domain, two RNA/DNA-recognition motifs, and a C-terminal intrinsically disordered region (IDR). Its structures have been partially determined, but the whole structure remains elusive. In this study, we investigate the possible end-to-end distance between the N- and C-termini of TDP-43, its alterations due to ALS-associated mutations in the IDR, and its apparent molecular shape in live cells using Förster resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS). Furthermore, the interaction between ALS-associated TDP-43 and heteronuclear ribonucleoprotein A1 (hnRNP A1) is slightly stronger than that of wild-type TDP-43. Our findings provide insights into the structure of wild-type and ALS-associated mutants of TDP-43 in a cell.
Topics: Humans; Amyotrophic Lateral Sclerosis; DNA-Binding Proteins; Mutation; Molecular Conformation; RNA
PubMed: 36982587
DOI: 10.3390/ijms24065513 -
Indian Journal of Pharmacology 2019Amyotrophic lateral sclerosis (ALS) is an untreatable and fatal neurodegenerative disease that is identified by the loss of motor neurons in the spinal cord, brain stem,... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is an untreatable and fatal neurodegenerative disease that is identified by the loss of motor neurons in the spinal cord, brain stem, and motor cortex which theatrically reduces life expectancy. Although the primary cause of ALS remains unclear, its heterogeneity put forward for consideration of association with various factors, including endogenous and/or environmental ones, which may be involved in progressive motor neuron stress that causes activation of different cell death pathways. It is hypothesized that this disease is triggered by factors related to genetic, environmental, and age-dependent risk. In spite of large neurobiological, molecular and genetic research, at the beginning of the 21 century, ALS still remains one of the most devastating neurodegenerative diseases because of the lack of effective therapeutic targets. It is a challenge for the clinical and scientific community. A better understanding of the etiology of ALS is necessary to develop specific targets of this progressive neurodegenerative disease. This review states about the current knowledge of targets in ALS research. This review provides an overview of the contribution of different targets like mitochondrial dysfunction, glutamate transport and excitotoxicity, protein accumulation, Oxidative stress, neuromuscular junction, microglia, and other molecular targets in the pathogenesis of ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Glutamic Acid; Humans; Mitochondria; Mutation; Neuromuscular Junction; Neuroprotective Agents; Oxidative Stress; Protein Aggregates; RNA
PubMed: 32029967
DOI: 10.4103/ijp.IJP_823_19 -
Brain and Behavior Dec 2023The causal relationship between work-related factors and amyotrophic lateral sclerosis (ALS) is unclear. We used a Mendelian randomization (MR) analysis to investigate...
BACKGROUND
The causal relationship between work-related factors and amyotrophic lateral sclerosis (ALS) is unclear. We used a Mendelian randomization (MR) analysis to investigate the unconfounded association between work-related factors and ALS.
METHODS
Univariable MR analyses were conducted to evaluate the causal effects of work-related factors on ALS. Instrumental variables from the UK Biobank on work-related factors (n = 263,615) were used as proxies. The outcome dataset used ALS (n case = 20,806, n control = 59,804) summary-level data from a large-scale genome-wide association study based on European ancestry. MR analysis used inverse variance weighted (IVW), MR-Egger, and weighted median (WM) to assess causal effects and other methods of MR for sensitivity analysis. Further multivariable MR analyses were performed to explore potential mediating effects.
RESULTS
In univariable MR, IVW methods support evidence that genetically determined job involves heavy manual or physical work (OR = 2.04, 95% CI: 1.26-3.31; p = .004) was associated with an increased risk of ALS, and the WM methods also confirm this result (OR = 2.36, 95% CI: 1.30-4.28; p = .005). No evidence of heterogeneity or horizontal pleiotropy was found in the results. In multivariable MR, the association was absent after adjusting for smoking and blood pressure.
CONCLUSIONS
Our MR analysis results demonstrate the potential causal relationship between jobs that involve heavy manual or physical work and ALS, which might be mediated by smoking and high systolic blood pressure.
Topics: Humans; Amyotrophic Lateral Sclerosis; Genome-Wide Association Study; Mendelian Randomization Analysis; Smoking; Tobacco Smoking; Polymorphism, Single Nucleotide
PubMed: 37960974
DOI: 10.1002/brb3.3317 -
Molecular Neurodegeneration Jan 2024Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Biomarkers; Motor Neurons
PubMed: 38267984
DOI: 10.1186/s13024-023-00685-6