Serum asymmetric dimethylarginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

Ikenaka, Kazuhiro; Maeda, Yasuhiro; Hotta, Yuji; Nagano, Seiichi; Yamada, Shinichiro; Ito, Daisuke; Torii, Ryota; Kakuda, Keita; Tatebe, Harutsugu; Atsuta, Naoki; Aguirre, César; Kimura, Yasuyoshi; Baba, Kousuke; Tokuda, Takahiko; Katsuno, Masahisa; Kimura, Kazunori; Sobue, Gen; Mochizuki, Hideki

doi:10.1111/ene.15254

Cited by 3 publications

(1 citation statement)

References 19 publications

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“…Further, protein arginine methylation activity has recently been implicated in ALS biomarker development. For example, higher levels of asymmetric dimethylarginine in cerebral spinal fluid (CSF) and serum have been shown to correlate faster progression of ALS symptoms ( Ikenaka et al, 2019 ; Ikenaka et al, 2022 ). Consistent with these results, asymmetrically (Type I) dimethylated forms of polyGR detected in C9orf72 patient brain tissue did not correlate with later disease onset or longer disease duration, in contrast to symmetrically (Type II) dimethylated forms of polyGR, which did ( Gittings et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Dane

Gill

Vieira

et al. 2023

Front. Cell. Neurosci.

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IntroductionIntronic repeat expansions in the C9orf72 gene are the most frequent known single genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeat expansions are believed to result in both loss-of-function and toxic gain-of-function. Gain-of-function results in the production of toxic arginine-rich dipeptide repeat proteins (DPRs), namely polyGR and polyPR. Small-molecule inhibition of Type I protein arginine methyltransferases (PRMTs) has been shown to protect against toxicity resulting from polyGR and polyPR challenge in NSC-34 cells and primary mouse-derived spinal neurons, but the effect in human motor neurons (MNs) has not yet been explored.MethodsTo study this, we generated a panel of C9orf72 homozygous and hemizygous knockout iPSCs to examine the contribution of C9orf72 loss-of-function toward disease pathogenesis. We differentiated these iPSCs into spinal motor neurons (sMNs).ResultsWe found that reduced levels of C9orf72 exacerbate polyGR15 toxicity in a dose-dependent manner. Type I PRMT inhibition was able to partially rescue polyGR15 toxicity in both wild-type and C9orf72-expanded sMNs.DiscussionThis study explores the interplay of loss-of-function and gain-of-function toxicity in C9orf72 ALS. It also implicates type I PRMT inhibitors as a possible modulator of polyGR toxicity.

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Section: Introductionmentioning

confidence: 99%

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Dane

Gill

Vieira

et al. 2023

Front. Cell. Neurosci.

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Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival

Waller,

Bury,

Appleby-Mallinder

et al. 2023

Brain Communications

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease, associated with the degeneration of both upper and lower motor neurons of the motor cortex, brainstem and spinal cord. Death in most patients results from respiratory failure within 3–4 years from symptom onset. However, due to disease heterogeneity some individuals survive only months from symptom onset while others live for several years. Identifying specific biomarkers that aid in establishing disease prognosis, particularly in terms of predicting disease progression, will help our understanding of amyotrophic lateral sclerosis pathophysiology and could be used to monitor a patient’s response to drugs and therapeutic agents. Transcriptomic profiling technologies are continually evolving, enabling us to identify key gene changes in biological processes associated with disease. MicroRNAs are small non-coding RNAs typically associated with regulating gene expression, by degrading mRNA or reducing levels of gene expression. Being able to associate gene expression changes with corresponding microRNA changes would help to distinguish a more complex biomarker signature enabling us to address key challenges associated with complex diseases such as amyotrophic lateral sclerosis. The present study aimed to investigate the transcriptomic profile (mRNA and microRNA) of lymphoblastoid cell lines from amyotrophic lateral sclerosis patients to identify key signatures that are distinguishable in those patients who suffered a short disease duration (<12 months) (n = 22) compared with those that had a longer disease duration (>6 years) (n = 20). Transcriptional profiling of microRNA–mRNA interactions from lymphoblastoid cell lines in amyotrophic lateral sclerosis patients revealed differential expression of genes involved in cell cycle, DNA damage and RNA processing in patients with longer survival from disease onset compared with those with short survival. Understanding these particular microRNA–mRNA interactions and the pathways in which they are involved may help to distinguish potential therapeutic targets that could exert neuroprotective effects to prolong the life expectancy of amyotrophic lateral sclerosis patients.

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Serum asymmetric dimethylarginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

Ikenaka

Maeda

Hotta

et al. 2022

Euro J of Neurology

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Background and purpose:The aim was to investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS.Methods: Serum ADMA levels of sporadic ALS patients (n = 68), disease control patients (n = 54) and healthy controls (n = 20) were measured using liquid chromatography tandem mass spectrometry. Correlations of the ADMA level and other markers (nitric oxide and neurofilament light chain levels) were analyzed. Changes in the ALS Functional Rating Scale Revised (ALSFRS-R) score from the onset of disease (ALSFRS-R pre-slope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan-Meier analysis. Results:The serum ADMA level was substantially higher in patients with ALS than in healthy controls and disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001) and was independently associated with the ALSFRS-R preslope (r = 0.505, p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF neurofilament light chain level (r = 0.456, p = 0.0002) but not with nitric oxide level (r = 0.194, p = 0.219).

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Serum asymmetric dimethylarginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

Cited by 3 publications

References 19 publications

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival

Serum asymmetric dimethylarginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

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