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Systematic review of gene expression studies in people with Lewy body dementia

Published online by Cambridge University Press:  17 March 2020

Anisa Chowdhury  and
Anto P. Rajkumar Open the ORCID record for Anto P. Rajkumar [Opens in a new window]
Anisa Chowdhury
Affiliation:
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, & Neuroscience, King’s College London, 16, De Crespigny Park, London-SE5 8AF, UK
Anto P. Rajkumar*
Affiliation:
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, & Neuroscience, King’s College London, 16, De Crespigny Park, London-SE5 8AF, UK Institute of Mental Health, Division of Psychiatry and Applied Psychology, University of Nottingham, Nottingham-NG7 2TU, UK
*
Author for correspondence: Anto P. Rajkumar, Email: [email protected]
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Abstract

Objectives:

Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer’s disease. Several genetic associations of LBD have been reported and their functional implications remain uncertain. Hence, we aimed to do a systematic review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.

Methods:

We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEGs) using Ingenuity Pathway Analyses.

Results:

We screened 3,809 articles and identified 31 eligible studies. In that, 1,242 statistically significant (p < 0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy–lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of ribonucleic acid (RNA)-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.

Conclusions:

α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research.

Keywords

Lewy body dementiaParkinson’s disease’ systematic reviewgene expressionRNA
Type
Review Article
Information
Acta Neuropsychiatrica , Volume 32 , Issue 6 , December 2020 , pp. 281 - 292
Copyright
© Scandinavian College of Neuropsychopharmacology 2020

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