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

Rahel Feleke, View ORCID ProfileRegina H. Reynolds, Amy Smith, Bension Tilley, View ORCID ProfileSarah A. Gagliano Taliun, John Hardy, Paul M. Matthews, Steve Gentleman, David Owen, Michael R. Johnson, Prashant Srivastava, Mina Ryten
doi: https://doi.org/10.1101/2021.04.22.440800
Rahel Feleke
1Department of Brain Sciences, Imperial College London, London, UK
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Regina H. Reynolds
2Department of Neurodegenerative Disease, University College London
3Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK
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  • ORCID record for Regina H. Reynolds
Amy Smith
5UK Dementia Research Institute at Imperial College London, London, UK
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Bension Tilley
1Department of Brain Sciences, Imperial College London, London, UK
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Sarah A. Gagliano Taliun
6Department of Medicine & Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada
7Montréal Heart Institute, Montréal, Québec, Canada
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  • ORCID record for Sarah A. Gagliano Taliun
John Hardy
2Department of Neurodegenerative Disease, University College London
8UK Dementia Research Institute at University College London, London, UK
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Paul M. Matthews
1Department of Brain Sciences, Imperial College London, London, UK
5UK Dementia Research Institute at Imperial College London, London, UK
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Steve Gentleman
1Department of Brain Sciences, Imperial College London, London, UK
5UK Dementia Research Institute at Imperial College London, London, UK
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David Owen
1Department of Brain Sciences, Imperial College London, London, UK
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Michael R. Johnson
1Department of Brain Sciences, Imperial College London, London, UK
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Prashant Srivastava
5UK Dementia Research Institute at Imperial College London, London, UK
9National Heart & Lung Institute, Imperial College London, London, UK
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Mina Ryten
3Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK
4NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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  • For correspondence: mina.ryten@ucl.ac.uk
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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.

Competing Interest Statement

RF, RHR, AS, BT, SAGT, JH, SG, DO, MRJ, PS and MR declare that they have no relevant financial or non-financial interests to disclose. PMM has received honoraria or consulting fees from Biogen, Novartis, Ipsen Pharmaceuticals, NodThera and Celgene. He receives research funding from Biogen, Merck, Celgene and Bristol Myers Squibb.

Footnotes

  • ↵# Shared first authors (alphabetical order)

  • + Shared last authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy Body diseases
Rahel Feleke, Regina H. Reynolds, Amy Smith, Bension Tilley, Sarah A. Gagliano Taliun, John Hardy, Paul M. Matthews, Steve Gentleman, David Owen, Michael R. Johnson, Prashant Srivastava, Mina Ryten
bioRxiv 2021.04.22.440800; doi: https://doi.org/10.1101/2021.04.22.440800
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Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy Body diseases
Rahel Feleke, Regina H. Reynolds, Amy Smith, Bension Tilley, Sarah A. Gagliano Taliun, John Hardy, Paul M. Matthews, Steve Gentleman, David Owen, Michael R. Johnson, Prashant Srivastava, Mina Ryten
bioRxiv 2021.04.22.440800; doi: https://doi.org/10.1101/2021.04.22.440800

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