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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE237570 | GEO | 2024/04/02

REPOSITORIES: GEO

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The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson’s disease

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2013-01-14 | E-GEOD-42912 | biostudies-arrayexpress

Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

Project description:Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nuclei transcriptomic analysis of human post-mortem in substantia nigra pars compacta (SNpc) tissue from 15 sporadic Parkinson’s Disease (PD) cases and 14 Controls. Our dataset comprised of ∼80K nuclei, representing all major cell types of the brain and allowed us to obtain a transcriptome-level characterization of these cell types. Importantly, we identified multiple subpopulations for each cell type and described subpopulation-specific gene sets that provide insights into the differing roles of these subpopulations. Our findings revealed a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrated a significant depletion of tyrosine hydroxylase (TH)-positive astrocyte, microglia, and oligodendrocyte populations, along with the TH-expressing neurons in PD samples, which were also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.

2024-01-22 | GSE243639 | GEO

Gene expression profiling of substantia nigra: a post-mortem study in Parkinson's disease and control subjects

Project description:Introduction: Parkinson's disease (PD) is characterized by bradykinesia, tremor, and rigidity; in addition, postural instability sets in as the disease progresses. Non-motor symptoms of the disease include cognitive, behavioral, and neuropsychiatric changes, sensory and sleep disturbances that may precede the motor symptoms of the disease itself. The peculiar pathological features of PD are decreased dopaminergic neurons and dopamine levels in the substantia nigra pars compacta and pontine locus ceruleus. The study of the transcriptome plays a major role in the identification of genes and gene regulatory mechanisms in multifactorial neurodegenerative diseases such as Parkinson's disease itself. Therefore, we proposed to study the transcriptome directly in the midbrain containing the "Substantia nigra.The study was performed in 8 subjects with PD and 6 normal control subjects, using next-generation sequencing (NGS) technologies. Results: With the use of an ad hoc bioinformatics pipeline, gene expression profiles in the different PD subjects were obtained and compared to those of controls. In detail, the results obtained from the data analysis indicated 92 differentially expressed genes (FDR-adjusted p value ≤0.05 and fold-change less than -1.5 or greater than +1.5) of which 33 genes were up-regulated while 59 were down-regulated. Conclusions: Functional analysis of the differentially expressed genes revealed several genes involved in different canonical pathways indicating their likely significant role in Parkinson's disease.

2024-01-03 | E-MTAB-13295 | biostudies-arrayexpress

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