Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

帕金森病（PD）、帕金森病伴痴呆（PDD）和路易体痴呆（DLB）是三种临床、遗传和神经病理学上重叠的神经退行性疾病，统称为路易体疾病（LBD）。PD 发病机制涉及多种分子机制，但 PDD 和 DLB 的潜在机制仍然很大程度上未知，这一知识差距阻碍了疾病缓解疗法的发现。转录组分析有助于解决这一差距，但在 LBD 中仍然有限。 在这里，我们对来自 28 名个体（包括健康对照、PD、PDD 和 DLB 病例（每组n = 7））的前扣带皮层样本应用配对的大块组织和单核 RNA 测序，以对 LBD 进行转录组分析。使用这种方法，我们 (i) 发现了 LBD 中多种细胞类型的转录改变；(ii) 发现了 RNA 剪接广泛失调的证据，特别是在 PDD 和 DLB 中；(iii) 确定了与其他痴呆相关神经退行性疾病相关的潜在剪接因子，协调了这种失调；(iv) 确定了 LBD 之间的转录组共性和区别，有助于理解这三种临床疾病之间的关系。总之，这些发现对于这些疾病的 RNA 靶向疗法的设计具有重要意义，并强调了 PD 最初发病和路易体痴呆后续发展之间潜在的分子治疗机会“窗口”。