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Base editing of Ptbp1 in neurons alleviates symptoms in a Parkinson’s disease mouse model

ABSTRACT: Base editing of Ptbp1 in neurons alleviates symptoms in a Parkinson’s disease mouse model

PROVIDER: PRJNA995757 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25307511_1.fastq.gz	Fastqsanger.gz
	SRR25307511_2.fastq.gz	Fastqsanger.gz
	SRR25307512_1.fastq.gz	Fastqsanger.gz
	SRR25307512_2.fastq.gz	Fastqsanger.gz
	SRR25307513_1.fastq.gz	Fastqsanger.gz

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Base editing of Ptbp1 in neurons alleviates symptoms in a Parkinson’s disease mouse model

Project description:Parkinson’s disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons. Recent studies reported successful conversion of astrocytes into dopaminergic neurons by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to a rescue of motor symptoms in a mouse model for PD. However, the mechanisms underlying this cell type conversion remain underexplored and controversial. Here, we devised a strategy using adenine base editing to effectively knockdown PTBP1 in astrocytes and neurons in a PD mouse model. Using AAV delivery vectors at a dose of 2´108 vg per animal, we found that Ptbp1 editing in neurons, but not astrocytes, of the substantia nigra pars compacta and striatum resulted in the formation of tyrosine hydroxylase (TH)+ cells and the rescue of forelimb akinesia and spontaneous rotations. Phenotypic analysis of TH+ cells indicates that they originated from non-dividing neurons and acquired dopaminergic neuronal markers upon PTBP1 downregulation. While further research is required to fully understand the origin, identity, and function of these newly generated TH+ cells, our study reveals that the downregulation of PTBP1 can reprogram neurons to mitigate symptoms in PD mice.

2024-04-02 | GSE237570 | GEO

iiCLIP protocol benchmarking with PTBP1

Project description:We describe an improved individual nucleotide resolution CLIP protocol (iiCLIP), which can be completed within 4 days from UV crosslinking to libraries for sequencing. For benchmarking, we directly compared PTBP1 iiCLIP libraries with the iCLIP2 protocol produced under standardised conditions with 1 million HEK293 cells, and with public eCLIP and iCLIP PTBP1 data. There are 3 PTBP1 iiCLIP libraries, 1 input iiCLIP library and 1 PTBP1 iCLIP2 library produced in this study.

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Targeting MLKL alleviates neuroinflammation and prevents motor neuron damage in Parkinson’s traits

Project description:Targeting MLKL alleviates neuroinflammation and prevents motor neuron damage in Parkinson’s traits

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Proteome changes in PTBP1 deficient hematopoietic cells

Project description:Ribosomopathies constitute a range of disabling conditions associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here we demonstrate that deletion of Polypyrimidine Tract Binding Protein 1 (PTBP1) in the hematopoietic compartment led to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 was associated with a decrease in HSC self-renewal, erythroid differentiation and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency led to splicing defects in hundreds of genes and we demonstrate that the up-regulation of a specific isoform of CDC42 could partly mimic the protein synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency was associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA binding proteins.

2022-05-04 | PXD023879 | Pride

PTBP1 - Modified iCLIP

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Regulation of co-transcriptional splicing by RNA-binding protein PTBP1

Project description:We examined the role of PTBP1 in regulation of co-transcriptional splicing process by depleting this RNA-binding protein from embryonic stem cells using the auxin-inducible degron technology and analysing the total and chromatin-associated RNA fractions by RNA-seq. We also performed mNET-seq and ChIP-seq analyses using RNA polymerase II- and PTBP1-specific antibodies, respectively. Our data suggest that PTBP1 activates co-transcriptional splicing of hundreds of introns, a surprising effect given that PTBP1 is better known as a splicing repressor. Importantly, some co-transcriptionally activated introns fail to be spliced post-transcriptionally without PTBP1. In a striking example of this regulation, lasting retention of a PTBP1-dependent intron triggers nonsense-mediated decay of mRNAs encoding DNA methyltransferase DNMT3B, explaining their natural expression dynamics in development. Our further analyses suggest that this mechanism may protect differentiation-specific genes from aberrant methylation. We conclude that PTBP1-activated co-transcriptional splicing underlies biologically important decisions.

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Project description:Neuroinflammatory processes are a prominent contributor to the pathology of Parkinson’s disease (PD), characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. MLKL-mediated cell necroptosis might occur in the onset of PD and lead to neuronal dopaminergic degeneration. However, the link between α-synuclein, neuroinflammatory processes, and neurodegeneration in PD remains unclear. Here, our in vitro study indicated that inhibition of MLKL exerted a protective effect against 6-OHDA- and TNF-α-induced neuronal cell death. Furthermore, we created a mouse model (Tg-Mlkl-/-) with typical progressive Parkinson traits by crossbreeding SNCA A53T transgenic mice with MLKL knockout mice. Tg-Mlkl-/ mice displayed dramatically improved motor symptoms and reduced hyperphosphorylated α-synuclein expression. More data suggested that MLKL deficiency protected dopaminergic neurons, blocked neuronal cell death, and attenuated neuroinflammation by inhibiting the activation of the microglia and astrocytes. Single-cell RNA-seq analysis revealed reduced microglial cells and damped neuron death in the SN of the Tg-Mlkl-/- mice. Subcluster analysis identified a unique cell type-specific transcriptome profiling in the MLKL deficiency mice. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing dopaminergic neuron degeneration.

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Transcriptomic analysis of senescent cells upon PTBP1 knockdown.

Project description:IMR90 ER:RAS cells were stably transduced with either an empty vector or 2 deconvoluted shRNAs targeting PTBP1. Following selection with puromycin, the cells were treated with 4OHT to induce senescence. 6 days later the cells were collected for total mRNA analysis. PTBP1 is a regulator of alternative splicing. Our previous experiments had shown that PTBP1 depletion inhibits the expression of pro-inflammatory genes without affecting other senescence-associated phenotypes. By performing RNA-seq we confirmed those observations at a global level and analysed how PTBP1 knockdown alters alternative splicing as a potential mechanism of action.

2018-06-25 | GSE101750 | GEO

Effect of degradation of IGFRIL/PTBP1 in HepG2 cells

Project description:To investigate the effect of IGFRIL/PTBP1 in HCC, we established HepG2 cell lines in which IGFRIL/PTBP1 mRNA has been degraded using siRNA.

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