Abstract
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.
Highlights
The Lewy body diseases (LBDs) comprise three neurodegenerative diseases, which are characterised by accumulation of Lewy bodies (α-synuclein-containing aggregates) in London, London, UK 9 National Heart and Lung Institute, Imperial College London, London, UK 10 Department of Neurosciences, Université de Montréal, Montréal, QC, Canada1 3 Vol.:(0123456789)Acta Neuropathologica (2021) 142:449–474 neurons and neuronal processes [55, 84]
We sampled from the anterior cingulate cortex, as it is one of the first cortical areas to be affected by α-synuclein pathology [6, 105] and a region where Lewy body densities correlate with cognitive impairment in Parkinson’s disease (PD) [59]
We (i) found transcriptional differences relative to controls for multiple cell types across the LBDs, with Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) more severely affected than PD; (ii) observed high levels of alternative splicing, in PDD and DLB; and (iii) identified splicing factors, with links to other dementia-related neurodegenerative diseases, that may coordinate these disease-related splicing changes
Summary
Acta Neuropathologica (2021) 142:449–474 neurons and neuronal processes [55, 84] These disorders, which include Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), have a prevalence in the general population aged ≥ 65 years of 2–3% [87], 0.3–0.5% [3] and 1–2% [55], respectively. While a variety of mechanisms, including mitochondrial and lysosomal dysfunction, oxidative stress, α-synuclein misfolding and neuroinflammation, have been implicated in PD pathogenesis [17, 87], less is known about the mechanisms underlying PDD and DLB Elucidating these mechanisms could provide a biological basis for the clinical distinction between PDD and DLB, which remains controversial in the field [14, 55, 56, 89, 112]. The overlap of these core clinical features could be evidence that the disorders are on a spectrum of disease, where DLB represents a more severe form of PDD
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