Mechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism

Tavasoli, Mahtab; Lahire, Sarah; Sokolenko, Stanislav; Novorolsky, Robyn J.; Reid, Sarah Anne; Lefsay, Abir; Otley, M O; Uaesoontrachoon, Kitipong; Rowsell, Joyce; Srinivassane, Sadish; Praest, Molly; MacKinnon, Alexandra; Mammoliti, Melissa; Maloney, Ashley; Moraca, Marina; Fernández-Murray, J. Pedro; McKenna, Meagan; Sinal, Christopher J.; Nagaraju, Kanneboyina; Robertson, Graham; Hoffman, Eric P.; McMaster, Christopher R.

doi:10.1038/s41467-022-29270-z

Cited by 13 publications

(15 citation statements)

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“…Elevated expression of nonsense-mediated decay transcripts CHKB-CPT1B and SLX1B-SULT1A4 in ALS-TD patients may implicate a TDP-43 associated mechanism similar to those detailed in the process of cryptic exon splicing in STMN2 and UNC13A 100 – 103 . Should this be the case, nonsense-mediated decay of read-through genes CHKB and CPT1B suggests deficits in mitochondrial lipid metabolism, known to play a pathogenic role in muscular dystrophy 104 , while loss of SLX1B and SULT1A4 indicate impaired genome stability and monoamine synthesis. Similarly, increased expression of retrotransposons, intronic, antisense, and long non-coding RNA implicates the TDP-43 protein in phenotypic presentation, given findings from Tam et al and others 7 , 99 .…”

Section: Discussionmentioning

confidence: 99%

Molecular subtypes of ALS are associated with differences in patient prognosis

et al. 2023

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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood clinical heterogeneity, underscored by significant differences in patient age at onset, symptom progression, therapeutic response, disease duration, and comorbidity presentation. We perform a patient stratification analysis to better understand the variability in ALS pathology, utilizing postmortem frontal and motor cortex transcriptomes derived from 208 patients. Building on the emerging role of transposable element (TE) expression in ALS, we consider locus-specific TEs as distinct molecular features during stratification. Here, we identify three unique molecular subtypes in this ALS cohort, with significant differences in patient survival. These results suggest independent disease mechanisms drive some of the clinical heterogeneity in ALS.

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Section: Discussionmentioning

confidence: 99%

Molecular subtypes of ALS are associated with differences in patient prognosis

et al. 2023

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“…CHKB-DT was divergently transcribed from CHKB. Homozygous loss-of-function variants in human CHKB were associated with congenital muscular dystrophy, dilated cardiomyopathy, and heart failure, 23,24 suggesting that CHKB-DT may also be a vital contributor to DCM pathogenesis.…”

Section: Novelty and Significancementioning

confidence: 99%

LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2

Nie,

Fan,

Dai

et al. 2024

Circulation Research

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Background: Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined. Methods: Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription–polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA–fluorescence in situ hybridization, and Western blotting. Results: CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction–induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and FUS (RNA-binding protein FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-hydroxy-2-nonenal production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT +/ − mice alleviated cardiac dilation and dysfunction. Conclusions: CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.

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“…In this issue of Circulation Research , Nie et al 1 from Dr Dao Wen Wang’s laboratory helped to broaden our understanding of the role of lncRNAs in the heart through their investigation into CHKB-DT—a noncoding transcript found in the same gene locus as CHKB . CHKB catalyzes the principal step of phosphatidylcholine and phosphatidylethanolamine de novo biosynthesis and has been found to contribute to a rare form of congenital muscular dystrophy 6 characterized by abnormalities in mitochondria structure 7 (Figure). A divergent transcript of CHKB , CHKB-DT, was previously identified by Dr Wang’s laboratory as a lncRNA that is highly downregulated in dilated cardiomyopathy (DCM) in human heart tissue samples.…”

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confidence: 99%