Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy Body diseases

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.

Consistent Abnormalities in Metabolic Patterns of Lewy Body Dementias

“…Together with significant pattern expression‐, volume‐, and voxel‐based correlations among three patterns, such metabolic similarities indicated the potential continuum within the clinical spectrum ranging from PD to DLB. Copathologies in PD, PDD, and DLB found in recent transcriptomic analysis, with identified postmortem molecular signatures enabling to distinguish PD from the two Lewy body dementias, 35 provided further support for our findings. Another difference between PDRP and DLBRP or PDDRP that required attention was the caudate.…”

Single-cell transcriptomic and proteomic analysis of Parkinson’s disease Brains

“…Similar trends have been described in the analysis of a PD midbrain dataset( 34 ). Also, significantly increased proportion of microglia has been found in a recent single cell study of anterior cingulate cortex across Lewy body diseases( 35 ). Many of the DEGs in oligodendrocytes and OPCs, encode GWAS hits such as MAPT and TMEM163 (Fig.…”

Neuronal identity defines α-synuclein and tau toxicity

“…The minimum gene set size was 10, maximum 500 and background defined by all detected genes in vulnerable and resilient neurons. GO terms with Benjamini-Hochberg adjusted p-values < 0.05 were retained and grouped by parent terms based on similarity and the 'Wang' method (Wang et al, 2007) in the mgoSim() function of the GOSemSim R package (v2.16.1) and the reduceSimMatrix() functions in the rrvgo (v1.2.0) package as implemented in the go_reduce() wrapper (Feleke et al, 2021).…”