Free amino acid levels in amyotrophic lateral sclerosis

Patten, Bernard M.; Harati, Yadollah; Acosta, Luis; Jung, Shin-Siung; Felmus, Mark T.

doi:10.1002/ana.410030405

Cited by 62 publications

(19 citation statements)

References 16 publications

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“…However three mutants, SOD1-G93A, SOD1-G85R and SOD1-G37R, that have been transduced into mice induce symptoms of motor neurodegeneration [39][40][41], although the mechanism by which this occurs remains unclear. Increased levels of tyrosine [19] Decreased levels of large neutral amino acids; no change in glutamate [20] Amino acids Increased levels of glutamate and serine; decreased levels of other amino acids [21] Cu/Zn superoxide dismutase (SOD1) 21q22.1 missense mutations [22] Fibronectin Decreased levels [23] Hyaluronic acid Increased levels [24] Interleukin 6 Increased levels: 73% sensitive, 91% specific [25] Plasma transforming growth factor-beta 1 Increased levels [26] 4-Hydroxy-2,3-nonenal Increased levels [27] Monocyte chemoattractant protein-1 Increased levels (not vs ND) [27] Angiogenin Increased levels [28] Interleukin 13-positive T cells Increased levels (CD4-positive and CD8-positive vs HC) [29] Insulin-like growth factor (IGF) and insulin-like growth factor-binding protein (IGFBP) Increased levels of total IGF and decreased levels of IGFBP (not vs ND) [30] Low-to high-density lipoprotein ratio Increased levels [31] Phosphorylated axonal neurofilament H subunit Increased levels [32] Heat shock proteins Increased levels [33] High-mortality group box 1 Increased inflammatory and neurodegenerative processes [34] TAR DNA-binding protein 43 (TDP-43) Genetic mutations [35] (RNA-binding protein FUS) FUS Genetic mutations [35] Despite this, there are several reasons why the loss of SOD1 activity may not be relevant to ALS: (a) SOD1 knockout mice do not present symptoms of motor neuron dysfunction [43]; (b) levels of SOD1 activity do not correlate with the disease in mice or humans [44]; and (c) an increase in SOD1 activity in the ALS mouse model does not accelerate or slow disease onset [45].…”

Section: Oxidative Stress and Copper/zinc-dependent Superoxide Dismutmentioning

confidence: 99%

Molecular Biomarkers for Amyotrophic Lateral Sclerosis

Hwang¹,

Hsieh²,

Liu³

et al. 2013

Current Bioinformatics

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Amyotrophic lateral sclerosis (ALS) is a complicated and devastating neurodegenerative disease. To date, its diagnosis is still mainly based on clinical symptoms and electromyographic findings. High rates of misdiagnosis and delayed diagnosis are the major hurdles in ALS treatment. Thus, searching for biomarkers to improve clinical diagnosis of ALS is a highly desirable goal. Here we review current potential biomarkers derived from the various pathogenic mechanisms of ALS, including those involved in oxidative stress, synaptic excitotoxicity, neuroinflammation and the autoimmune response. Oxidative stress results from genetic mutation or an increase in protein aggregation, synaptic excitotoxicity arising from elevated levels of glutamate and D-serine, and the neuroinflammation occurring from elevated levels of inflammatory molecules and cytokine receptors. Some of these biomarkers could be used for monitoring the disease progression and to assess effectiveness of treatment for ALS. We conclude that neuroinflammation plays a crucial role in ALS, which may lead to a better understanding of this devastating disease and ultimately to a cure. In addition, the identification of new biomarkers would undoubtedly provide critical insights into the pathogenesis of ALS.

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Section: Oxidative Stress and Copper/zinc-dependent Superoxide Dismutmentioning

confidence: 99%

Molecular Biomarkers for Amyotrophic Lateral Sclerosis

Hwang¹,

Hsieh²,

Liu³

et al. 2013

Current Bioinformatics

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“…64 This study, aimed at comparing amino acid levels in 12 ALS patients with those of 12 control patients, matched for age, sex, and severity of disability (affected by diverse paralytic disorders), reports that glutamate concentrations are unchanged in cerebrospinal fluid (CSF) and not significantly increased in serum and urine, suggesting that there is no glutamate-associated specific signature in ALS patients. However, this was challenged a decade later, when plasma 65 and CSF 66 glutamate levels of 18 to 22 ALS patients were shown to be doubled compared to healthy controls and other neurological disorders patients.…”

Section: Glutamate and Als: History And Controversiesmentioning

confidence: 99%

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Verche¹,

Ikiz²,

Jacquier³

et al. 2010

JRLCR

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Abstract:The cause of the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), remains largely unknown. Most cases of ALS are sporadic and, for ∼20% of familial ALS patients, mutations in the superoxide dismutase-1 (SOD1) gene have been identified. Transgenic rodents overexpressing mutant SOD1 emulate the disease and constitute the best ALS animal model so far. Several lines of evidence suggest that ALS is a multifactorial condition. In this review, we discuss the question of the involvement of the glutamate pathways in ALS-induced motor neuron death. As such, we review the data implicating glutamate metabolism alterations, glutamatergic environmental toxins, glutamate transporter/receptor defects, and Ca 2+ -mediated glutamate toxicity in the etiopathogenesis of ALS. Given the published data, we contend that glutamate-induced neurotoxicity more likely precipitates motor neuron degeneration rather than being the initiating factor of ALS. Furthermore, we propose that glutamate-induced neurotoxicity participates in the ALS deadly molecular cascade only as an executioner to put an end to a series of molecular perturbations that have irreversibly compromised motor neuron function. This could provide an explanation for the modest effect of therapeutic strategies targeting the glutamatergic system, including the only currently FDA-approved ALS treatment, riluzole. As in diseased motor neurons, overwhelming Ca 2+ overload may be the converging point for glutamate, endoplasmic reticulum stress, and mitochondrial dysfunctional pathways, and only therapies targeting these simultaneously or targeting the earliest alterations initiating this deleterious cascade may have a real impact on halting ALS progression.

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“…The severity of disability was rated from 1 to 4 at the time the skin samples were obtained: 1 = little or no interference with work and daily activities; 2 = moderate interference with work and daily activities but able to work and able to earn a living for self; 3 = severe interference with daily activities, unable to work but able to do some things for self, and 4 = totally dependent on others for care [15]. Severities of disability were 3.1 ± 0.9 in ALS patients and 2.8 ± 1.1 in control group A.…”

Section: Methodsmentioning

confidence: 99%

Serum Markers of Type I Collagen Synthesis and Degradation in Amyotrophic Lateral Sclerosis

Ono¹,

Imai²,

Shimizu³

et al. 2000

Eur Neurol

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Collagen abnormalities in the skin and spinal cord have been reported in amyotrophic lateral sclerosis (ALS) patients. Serum carboxyterminal propeptide of type I procollagen (PICP) and the carboxyterminal cross-linked telopeptide of type I collagen (ICTP) reflect type I collagen synthesis and degradation, respectively. However, there has been no study concerning PICP or ICTP in ALS. We studied collagen contents of the skin and measured serum levels of PICP and ICTP in patients with ALS and control subjects. Serum PICP levels were significantly lower in ALS patients than in controls. Serum ICTP levels were significantly higher in ALS patients than in controls, and there was an appreciable positive correlation between serum ICTP levels and the duration of illness in ALS patients. In ALS patients, the collagen content of the skin was significantly smaller than in controls and indicated a progressive decrease in relation to illness. In addition, there was a significant negative correlation between serum ICTP concentrations and the collagen content of the skin in ALS patients. These data suggest that increased ICTP levels and decreased serum PICP levels may reflect unique changes in the skin, with a predominance of degradation compared to the synthesis of type I collagen in ALS.

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Free amino acid levels in amyotrophic lateral sclerosis

Cited by 62 publications

References 16 publications

Molecular Biomarkers for Amyotrophic Lateral Sclerosis

Molecular Biomarkers for Amyotrophic Lateral Sclerosis

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Serum Markers of Type I Collagen Synthesis and Degradation in Amyotrophic Lateral Sclerosis

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