Reduced levels of ALS gene DCTN1 induce motor defects in Drosophila
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA936879 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23558735_1.fastq.gz | Fastqsanger.gz | |||
| SRR23558735_2.fastq.gz | Fastqsanger.gz | |||
| SRR23558736_1.fastq.gz | Fastqsanger.gz | |||
| SRR23558736_2.fastq.gz | Fastqsanger.gz | |||
| SRR23558737_1.fastq.gz | Fastqsanger.gz |
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Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuromuscular disease that has a strong genetic component. Deleterious variants in the DCTN1 gene are known to be a cause of ALS in diverse populations. DCTN1 encodes the p150 subunit of the molecular motor dynactin which is a key player in the bidirectional transport of cargos within cells. Whether DCTN1 mutations lead to the disease through either a gain or loss of function mechanism remains unresolved. Moreover, the contribution of non neuronal cell types, especially muscle tissue, to ALS phenotypes in DCTN1 carriers is unknown. Here we show that gene silencing of Dctn1, the Drosophila main orthologue of DCTN1, either in neurons or muscles is sufficient to cause climbing and flight defects in adult flies. We also identify Dred, a protein with high homology to Drosophila Dctn1 and human DCTN1, that on loss of function also leads to motoric impairments. A global reduction of Dctn1 induced a significant reduction in the mobility of larvae and neuromuscular junction (NMJ) deficits prior to death at the pupal stage. RNA-seq and transcriptome profiling revealed splicing alterations in genes required for synapse organisation and function, which help explain the observed motor dysfunction and synaptic defects downstream of Dctn1 ablation. Our findings support the possibility that loss of DCTN1 function can lead to ALS and underscore an important requirement for DCTN1 in muscle in addition to neurons.
2023-06-28 | GSE225648 | GEO
Project description:Recent genetic studies of ALS patients have identified several forms of ALS that are associated with mutations in RNA binding proteins. In animals or cultured cells, such defects broadly affect RNA metabolism. This raises the question of whether all forms of ALS have general effects on RNA metabolism. We tested this hypothesis in a mouse model of ALS that is transgenic for a human disease-causing mutation in the enzyme superoxide dismutase 1 (SOD1). We analyzed RNA from laser-captured spinal cord motor neuron cell bodies of the mutant SOD1 strain, comparing the RNA profile with that from a corresponding wild-type SOD1 transgenic strain. We prepared the samples from animals that were presymptomatic, but which manifested abnormalities at the cellular level that are seen in ALS, including aggregation of the mutant protein in motor neuron cell bodies and defective morphology of neuromuscular junctions, the connections between neuron and muscle. We observed only minor changes in the level and splicing of RNA in the SOD1 mutant animals as compared with wild-type, suggesting that mutant SOD1 produces the toxic effects of ALS by a mechanism that does not involve global RNA disturbance. RNA-Seq of laser microdissection of motor neuron bodies from two biological replicates each of SOD1 YFP (wildtype 592) and SOD1 G85R YFP (737) transgenic mice.
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Project description:Differentiated motor neurons from hiPSC derived from peripheral nerve fibroblasts of sporadic ALS patients and evaluated the gene expression profile by means microarray-linked to specific analysis tools. Two-condition experiment, ALS patients motor neurons vs. controls. Biological replicates: 3 ALS replicates, 3 control replicates.
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Project description:Gene expression profiling has been performed on motor cortex and spinal cord homogenates and of sporadic ALS cases and controls, to identify genes and pathways differentially expressed in ALS. More recent studies have combined the use of laser capture microdissection (LCM) with gene expression profiling to isolate the motor neurons from the surrounding cells, such as microglia and astrocytes, in order to determine those genes differentially expressed in the vulnerable cell population â i.e. motor neuron. The aim of this study was to determine the gene expression profiles from a small subset of cases which all carry mutations in the CHMP2B gene. These mutations have been found to be associated with the lower motor neuron dominant variant of ALS. Expression profiles from isolated motor neurons in CHMP2B-related ALS cases were compared to those from control motor neurons, in order to establish the pathways implicated in CHMP2B-related motor neuronal cell death.
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Project description:Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) degenerative disease with a major pathological feature of cytoplasmic TDP-43 aggregation. However, the mechanisms underlying TDP-43 proteinopathy are still largely unknown. We performed in vitro differentiation of ALS-induced pluripotent stem cells (ALS-iPSCs; carrying the TDP-43M337V mutation) and isogenic controls and found upregulation of paraspeckle-associated lncRNA NEAT1 isoforms in the ALS-iPSC-derived MNs (ALS-iPSC-MNs). Intriguingly, the upregulated NEAT1 isoforms were mislocalized to the cytoplasm of ALS-iPSC-MNs, and the cytoplasmic NEAT1 provoked TDP-43 and TDP-43M337V liquid-liquid phase separation, generating long-lived protein condensates. These condensates had reduced mobility and were converted into aggregates, finally co-aggregating with phospho-TDP-43. Disruption of NEAT1 expression reduced its cytoplasmic levels and also reduced the levels of TDP-43/TDP-43M337V condensates. In 3D neuromuscular organoids with the TDP-43M337V mutation, treatment with NEAT1-antisense oligonucleotides (NEAT1-ASO) promoted neuromuscular junction formation and function, as well as muscle contractility. Furthermore, treatment of TDP-43Q331K mice with Neat1-ASO attenuated TDP-43 pathology in spinal cord and preserved motor function. These findings suggest that NEAT1 plays an important role in TDP-43-associated pathology, and NEAT1-ASO may attenuate pathological TDP-43 aggregation to prevent motor neuron degeneration and muscle weakness in ALS.
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Project description:Recent genetic studies of ALS patients have identified several forms of ALS that are associated with mutations in RNA binding proteins. In animals or cultured cells, such defects broadly affect RNA metabolism. This raises the question of whether all forms of ALS have general effects on RNA metabolism. We tested this hypothesis in a mouse model of ALS that is transgenic for a human disease-causing mutation in the enzyme superoxide dismutase 1 (SOD1). We analyzed RNA from laser-captured spinal cord motor neuron cell bodies of the mutant SOD1 strain, comparing the RNA profile with that from a corresponding wild-type SOD1 transgenic strain. We prepared the samples from animals that were presymptomatic, but which manifested abnormalities at the cellular level that are seen in ALS, including aggregation of the mutant protein in motor neuron cell bodies and defective morphology of neuromuscular junctions, the connections between neuron and muscle. We observed only minor changes in the level and splicing of RNA in the SOD1 mutant animals as compared with wild-type, suggesting that mutant SOD1 produces the toxic effects of ALS by a mechanism that does not involve global RNA disturbance.
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Project description:Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. It has a strong genetic contribution, but most ALS-associated gene mutations remain poorly characterized. Therefore, we performed comparative interactome analyses of recently discovered ALS-associated proteins which highlighted many novel binding partners, and both unique and shared interactors. This suggests that different ALS-associated proteins can act through distinct and/or similar cellular pathways. The analysis identified C21ORF2 as a strongly connected protein. The role of C21ORF2 mutations in ALS is largely unknown. Our data show C21ORF2 expression in affected neurons and that the prominent C21ORF2-V58L variant induces apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response (DDR), mitochondria and electrophysiological properties. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our data define the pathogenic effects of C21ORF2-V58L and implicate reduced NEK1 levels, due to impaired proteosomal degradation, downstream of this ALS mutation.
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