TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1.
TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1.
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DOI：
10.1371/journal.pgen.1010973
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发表时间：
2023-09
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影响因子：
4.5
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在包括肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）和阿尔茨海默病（AD）在内的一系列神经退行性疾病的神经元和胶质细胞中，都可见到TAR-DNA结合蛋白43 （TDP-43）胞质内含物的积累。疾病进展涉及多种细胞类型之间的非细胞自主相互作用，包括神经元、小胶质细胞和星形胶质细胞。我们研究了可诱导的、胶质细胞类型特异性的TDP-43过表达对果蝇的影响，该模型导致TDP-43蛋白病理，包括核TDP-43的丢失和细胞质包涵体的积累。我们报道，TDP-43在果蝇中的病理足以导致5种胶质亚型中的每一种的进行性损失。但当TDP-43在神经周围胶质细胞（PNG）或星形胶质细胞中引起病变时，对机体存活的影响最为明显。在PNG的情况下，这种影响不是由于胶质细胞群的损失，因为通过表达促凋亡reaper表达来消融这些胶质细胞对存活的影响相对较小。为了揭示潜在的机制，我们使用细胞类型特异性核RNA测序来表征病理性TDP-43表达诱导的转录变化。我们发现了许多胶质细胞类型特异性的转录变化。值得注意的是，PNG和星形胶质细胞中SF2/SRSF1水平均下降。我们发现，在PNG或星形胶质细胞中进一步敲低SF2/SRSF1可以减轻TDP-43病理对寿命的有害影响，但可以延长胶质细胞的存活时间。因此，星形胶质细胞或PNG中的TDP-43病理会导致缩短寿命的全身性影响，而SF2/SRSF1的敲低挽救了这些胶质细胞的损失，并降低了它们对生物体的全身性毒性。神经退行性疾病，如肌萎缩性侧索硬化症（ALS）、额颞叶痴呆（FTD）和阿尔茨海默病（AD）涉及大脑中神经元和非神经元细胞的功能障碍。这些疾病中的每一种都涉及一种名为TDP-43的蛋白质的异常积累，这种蛋白质被认为会导致最终导致细胞死亡的毒性作用。我们使用细胞类型特异性测序来表征在果蝇的每种非神经元细胞类型中诱导病理性TDP-43的影响。这项研究确定了SF2/SRSF1基因表达的变化，该基因先前被认为与介导毒性作用有关。我们发现，在单个神经胶质细胞类型中敲低该基因的表达足以防止附近神经元的丢失。
Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects in Drosophila of inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology in Drosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown of SF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan and SF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism. Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD) involve dysfunction in both neuronal and non-neuronal cells in the brain. Each of these disorders involves abnormal accumulation of a protein called TDP-43, which is thought to cause toxic effects that ultimately lead to cell death. We used cell type specific sequencing to characterize the effects of inducing pathological TDP-43 within each of the non-neuronal cell types in Drosophila. This identified changes in expression of a gene called SF2/SRSF1, which has previously been implicated in mediating toxic effects. We found that knocking down the expression of this gene within individual glial cell types was sufficient to prevent the loss of nearby neurons.