Distinct circular DNA profile in hSOD1G93A ALS that intersects with ALS proteome changes
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ABSTRACT:
PROVIDER: PRJNA886738 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21789900_1.fastq.gz | Fastqsanger.gz | |||
| SRR21789900_2.fastq.gz | Fastqsanger.gz | |||
| SRR21789901_1.fastq.gz | Fastqsanger.gz | |||
| SRR21789901_2.fastq.gz | Fastqsanger.gz | |||
| SRR21789902.fastq.gz | Fastqsanger.gz |
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Project description:Numerous genes mutated in amyotrophic lateral sclerosis (ALS) share a role in DNA damage and repair, emphasizing genome disintegration in ALS. DNA instability and repair mechanisms segregate extrachromosomal circular DNAs (ec/eccDNAs) that can modulate gene expression somatically. Here, circulome profiling in a hSOD1G93A genotoxicity model of ALS revealed a 6-fold enrichment of small-size eccDNAs relative to controls. DifCir-based differential analysis identified 189 genes with patterned segregation of differentially produced per gene circles (DPpGCs) from ALS but not from control samples, implicating an inter-sample recurrence rate of at least 89% for the top 6 DPpGCs. Mass spectrometry-based ALS circulome-proteome cross-referencing revealed 31 corresponding differentially expressed proteins (DEPs), with 12 DPpGC-DEP pairs being itemized in ALS risk GWAS databases. DPpGC-DEP hotspots mainly convey neuron-specific functions counteracting ALS detriments. This is unanticipated evidence for non-random, profiled eccDNA accumulation in ALS neurodegeneration, involving putative interactions with their gene products as well as biomarker perspectives.
2023-09-20 | GSE214718 | GEO
Project description:BackgroundNumerous genes, including SOD1, mutated in familial and sporadic amyotrophic lateral sclerosis (f/sALS) share a role in DNA damage and repair, emphasizing genome disintegration in ALS. One possible outcome of chromosomal instability and repair processes is extrachromosomal circular DNA (eccDNA) formation. Therefore, eccDNA might accumulate in f/sALS with yet unknown function.MethodsWe combined rolling circle amplification with linear DNA digestion to purify eccDNA from the cervical spinal cord of 9 co-isogenic symptomatic hSOD1G93A mutants and 10 controls, followed by deep short-read sequencing. We mapped the eccDNAs and performed differential analysis based on the split read signal of the eccDNAs, referred as DifCir, between the ALS and control specimens, to find differentially produced per gene circles (DPpGC) in the two groups. Compared were eccDNA abundances, length distributions and genic profiles. We further assessed proteome alterations in ALS by mass spectrometry, and matched the DPpGCs with differentially expressed proteins (DEPs) in ALS. Additionally, we aligned the ALS-specific DPpGCs to ALS risk gene databases.ResultsWe found a six-fold enrichment in the number of unique eccDNAs in the genotoxic ALS-model relative to controls. We uncovered a distinct genic circulome profile characterized by 225 up-DPpGCs, i.e., genes that produced more eccDNAs from distinct gene sequences in ALS than under control conditions. The inter-sample recurrence rate was at least 89% for the top 6 up-DPpGCs. ALS proteome analyses revealed 42 corresponding DEPs, of which 19 underlying genes were itemized for an ALS risk in GWAS databases. The up-DPpGCs and their DEP tandems mainly impart neuron-specific functions, and gene set enrichment analyses indicated an overrepresentation of the adenylate cyclase modulating G protein pathway.ConclusionsWe prove, for the first time, a significant enrichment of eccDNA in the ALS-affected spinal cord. Our triple circulome, proteome and genome approach provide indication for a potential importance of certain eccDNAs in ALS neurodegeneration and a yet unconsidered role as ALS biomarkers. The related functional pathways might open up new targets for therapeutic intervention.
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Project description:There is increasing evidence on the role of circular RNAs (circRNAs) in neuronal and muscular processes. Accordingly, their dysregulation is associated with neurodegenerative diseases and myopathies. We investigated circRNA expression in the central nervous system (CNS) and skeletal muscle, the two main tissues affected in amyotrophic lateral sclerosis (ALS). Based on circRNA sequencing analysis in spinal cord from ALS mice (SOD1G93A) followed by a literature search, 30 circRNAs potentially involved in ALS were tested. All selected circRNAs were downregulated in the SOD1G93A spinal cord, whereas only half of these were quantifiable and were generally upregulated in quadriceps muscle of SOD1G93A mice. Such tissue-dependent expression pattern was observed in both sexes and circRNA abundance in the spinal cord was higher than in the muscle, both in wild type and in SOD1G93A mice. Finally, we assessed the 18 circRNAs with the largest expression differences and the highest degree of interspecies conservation in brain samples from sporadic ALS (sALS) patients and healthy controls. Similar to the mouse model, circRNA levels tended to decrease in the CNS of sALS patients. Expression of circRNAs may be systematically altered in the two tissues most affected by ALS in a progressive and opposed manner. Although more detailed studies are warranted, circRNAs are potentially related to ALS etiopathogenesis and could possibly serve as future biomarkers, therapeutic targets, or customized therapeutic tools to modulate the pathology.
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Project description:The purpose of this experiment was to compare the differences in transcript levels between RNA samples collected from fibroblasts from healthy control patients, amyotrophic lateral sclerosis (ALS) patients carrying an expanded GGGGCC repeat mutation in the chromosome 9 open reading frame 72 gene and ALS patients with a mutation in the SOD1 gene.
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Project description:Loss-of-function variants in TBK1, encoding a serine/threonine protein kinase, are strongly associated with sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the targets of TBK1 in neurons are unknown, and how haploinsufficiency for TBK1 leads to age-related neurodegeneration remains unresolved. Here, we utilized sets of isogenic induced pluripotent stem cells (iiPSCs) with loss of TBK1 or loss of optineurin (OPTN) for quantitative proteomics and phospho-proteomics across tens of thousands of phospho-sites in proliferating stem cells and induced excitatory neurons. We found that TBK1 sustains the abundance and phosphorylation of its interacting adapter proteins, AZI2/NAP1, TBKBP1, and TANK1, in the cellular context of neurons. Moreover, TBK1 regulates the phosphorylation of selective autophagy proteins, particularly at novel phospho-serine residues within cargo receptors, and endo-lysosomal pathways, including the late-endosome GTPase RAB7A, in human neurons. Additionally, we observed that the disease-associated TBK1 G217R variant acts as a phospho-protein quantitative trait locus (ppQTL) for the phosphorylation status of familial ALS-associated proteins p62/SQSTM1 and OPTN, as well as GABARAPL2, an Atg8- family autophagy protein. Furthermore, we demonstrate that TBK1 is required for neurite outgrowth and lysosomal function. Finally, we provide a census of the phospho-proteome in nascent human neurons for further dissection of protein phosphorylation in neural-enriched proteins, such as tau, in neurological and psychiatric disorders. These studies provide a global view of TBK1 as a central point of convergence in ALS/FTD-linked endo-lysosomal networks that act in a cell-autonomous manner to maintain protein homeostasis in neurons.
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Project description:Circular RNAs are abundant, covalently closed transcripts that arise in cells through back-splicing and display distinct expression patterns across cells and developmental stages. While their functions are largely unknown, their intrinsic stability has made them valuable biomarkers in diseases like cancer. Here, we set out to examine circRNA patterns in amyotrophic lateral sclerosis (ALS). By RNA-sequencing analysis, we first identified circRNAs and linear RNAs that were differentially abundant in skeletal muscle biopsies from ALS and normal individuals. Among these, 8 circRNAs were significantly elevated and 10 significantly reduced in ALS, while the linear counterparts, arising from shared precursor RNAs, did not change. Several of these circRNAs were also differentially abundant in motor neurons derived from human induced pluripotent stem cells (iPSCs) bearing ALS mutations, and across different disease stages in skeletal muscle from a mouse model of ALS (SOD1G93A). Interestingly, several of the circRNAs significantly elevated in muscle were significantly reduced in the spinal cord from ALS patients and ALS (SOD1G93A) mice. In sum, we have identified differentially abundant circRNAs in ALS-relevant tissues (muscle and spinal cord) that could inform about neuromuscular molecular programs in ALS and guide the development of therapies.
2023-02-01 | GSE215364 | GEO
Project description:Circular RNAs are abundant, covalently closed transcripts that arise in cells through back-splicing and display distinct expression patterns across cells and developmental stages. While their functions are largely unknown, their intrinsic stability has made them valuable biomarkers in diseases like cancer. Here, we set out to examine circRNA patterns in amyotrophic lateral sclerosis (ALS). By RNA-sequencing analysis, we first identified circRNAs and linear RNAs that were differentially abundant in skeletal muscle biopsies from ALS and normal individuals. Among these, 8 circRNAs were significantly elevated and 10 significantly reduced in ALS, while the linear counterparts, arising from shared precursor RNAs, did not change. Several of these circRNAs were also differentially abundant in motor neurons derived from human induced pluripotent stem cells (iPSCs) bearing ALS mutations, and across different disease stages in skeletal muscle from a mouse model of ALS (SOD1G93A). Interestingly, several of the circRNAs significantly elevated in muscle were significantly reduced in the spinal cord from ALS patients and ALS (SOD1G93A) mice. In sum, we have identified differentially abundant circRNAs in ALS-relevant tissues (muscle and spinal cord) that could inform about neuromuscular molecular programs in ALS and guide the development of therapies.
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