40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Kwong, Koy Chong Ng Kee; Harbham, Pratap K.; Selvaraj, Bhuvaneish T.; Gregory, Jenna M; Pal, Suvankar; Hardingham, Giles E.; Chandran, Siddharthan; Mehta, Arpan R.

doi:10.3389/fnmol.2021.647895

Cited by 13 publications

(4 citation statements)

References 96 publications

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“…This heterogeneity was observed in both ALS and control subjects and could not be explained by the analytical incertitude of our method [ 24 ]. Many investigations assessing glutamic acid levels in the CSF of ALS subjects have been performed but its relationship with glutamate-mediated excitotoxicity is unclear [ 25 ]. Considering the heterogeneity of both ALS patients and controls, all suffering from brain disorders, we suggest that glutamic acid, i.e., one of the most important neurotransmitters is highly variable.…”

Section: Discussionmentioning

confidence: 99%

Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis

et al. 2021

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The aim of this study was to evaluate the kynurenine pathway (KP) and amino acids profile, using mass spectrometry, in the cerebrospinal fluid (CSF) of 42 amyotrophic lateral sclerosis (ALS) patients at the diagnosis and 40 controls to detect early disorders of these pathways. Diagnostic and predictive ability (based on weight loss, forced vital capacity, ALS Functional Rating Scale—Revised evolution over 12 months, and survival time) of these metabolites were evaluated using univariate followed by supervised multivariate analysis. The multivariate model between ALS and controls was not significant but highlighted some KP metabolites (kynurenine (KYN), kynurenic acid (KYNA), 3-Hydroxynurenine (3-HK)/KYNA ratio), and amino acids (Lysine, asparagine) as involved in the discrimination between groups (accuracy 62%). It revealed a probable KP impairment toward neurotoxicity in ALS patients and in bulbar forms. Regarding the prognostic effect of metabolites, 12 were commonly discriminant for at least 3 of 4 disease evolution criteria. This investigation was crucial as it did not show significant changes in CSF concentrations of amino acids and KP intermediates in early ALS evolution. However, trends of KP modifications suggest further exploration. The unclear kinetics of neuroinflammation linked to KP support the interest in exploring these pathways during disease evolution through a longitudinal strategy.

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Section: Discussionmentioning

confidence: 99%

Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis

et al. 2021

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“…The implication that circulating toxins might be responsible for the degeneration of the anterior horn cells was based on the seminal observation of Wolfgram and Myers describing that diluted serum, specifically from ALS patients, had a toxic effect on mouse anterior horn cells in culture [ 24 ]. From the efforts to model sporadic ALS based on circulating agents, those based either on the effect of cerebrospinal fluids [ 25 , 26 ] or of sera from the patients [ 27 ] can be emphasized. Indeed, a line of research data from Appel’s laboratory documented the presence of immunoglobulins in spinal and cortical motor neurons [ 28 ] and the ability of immunoglobulins from sporadic ALS patients (i) to induce apoptotic cell death in a hybrid motoneuron cell line [ 29 ], (ii) to increase the Ca 2+ current [ 30 ] and calcium level in motoneurons in vitro [ 31 ], and (iii) to increase the intracellular calcium of cell bodies and axon terminals of MNs and the increase in synaptic vesicles at the neuromuscular synapses, in vivo [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Passive Transfer of Blood Sera from ALS Patients with Identified Mutations Results in Elevated Motoneuronal Calcium Level and Loss of Motor Neurons in the Spinal Cord of Mice

Polgár

Meszlényi

Nógrádi

et al. 2021

IJMS

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Introduction: Previously, we demonstrated the degeneration of axon terminals in mice after repeated injections of blood sera from amyotrophic lateral sclerosis (ALS) patients with identified mutations. However, whether a similar treatment affects the cell body of motor neurons (MNs) remained unresolved. Methods: Sera from healthy individuals or ALS patients with a mutation in different ALS-related genes were intraperitoneally injected into ten-week-old male Balb/c mice (n = 3/serum) for two days. Afterward, the perikaryal calcium level was measured using electron microscopy. Furthermore, the optical disector method was used to evaluate the number of lumbar MNs. Results: The cytoplasmic calcium level of the lumbar MNs of the ALS-serum-treated mice, compared to untreated and healthy-serum-treated controls, was significantly elevated. While injections of the healthy serum did not reduce the number of MNs compared to the untreated control group, ALS sera induced a remarkable loss of MNs. Discussion: Similarly to the distant motor axon terminals, the injection of blood sera of ALS patients has a rapid degenerative effect on MNs. Analogously, the magnitude of the evoked changes was specific to the type of mutation; furthermore, the degeneration was most pronounced in the group treated with sera from ALS patients with a mutation in the chromosome 9 open reading frame 72 gene.

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“…Generally, the onset of this disease is in adulthood, and 3-5 years is the average time ALS patients survive after diagnosis. The neurodegenerative pathology for ALS includes excitotoxicity, hyperexcitability, neuroinflammation, mitochondrial dysfunction, axonal growth, functional defects, and dysregulated autophagy [70][71][72][73][74]. ALS patients include two categories namely familial ALS (FALS), and sporadic ALS (SALS).…”

Section: The Use Of Gene Editing For Alsmentioning

confidence: 99%

Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

Karpe

Chen

2021

Pharmaceuticals

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Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.

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40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Cited by 13 publications

References 96 publications

Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis

Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis

Passive Transfer of Blood Sera from ALS Patients with Identified Mutations Results in Elevated Motoneuronal Calcium Level and Loss of Motor Neurons in the Spinal Cord of Mice

Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

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