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Cited by 98Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Systematic review and meta-analysis of human transcriptomics reveals neuroinflammation, deficient energy metabolism, and proteostasis failure across neurodegeneration

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Noori, Ayush, Mezlini, Aziz M., Hyman, Bradley T., Serrano-Pozo, Alberto, Das, Sudeshna·2021·Neurobiology of Disease
DOI 10.1016/j.nbd.2020.105225PMC PMC7856076
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Abstract

Neurodegenerative disorders such as Alzheimer's disease (AD), Lewy body diseases (LBD), and the amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) spectrum are defined by the accumulation of specific misfolded protein aggregates. However, the mechanisms by which each proteinopathy leads to neurodegeneration remain elusive. We hypothesized that there is a common "pan-neurodegenerative" gene expression signature driving pathophysiology across these clinically and pathologically diverse proteinopathies. To test this hypothesis, we performed a systematic review of human CNS transcriptomics datasets from AD, LBD, and ALS-FTD patients and age-matched controls in the Gene Expression Omnibus (GEO) and ArrayExpress databases, followed by consistent processing of each dataset, meta-analysis, pathway enrichment, and overlap analyses. After applying pre-specified eligibility criteria and stringent data pre-processing, a total of 2600 samples from 26 AD, 21 LBD, and 13 ALS-FTD datasets were included in the meta-analysis. The pan-neurodegenerative gene signature is characterized by an upregulation of innate immunity, cytoskeleton, and transcription and RNA processing genes, and a downregulation of the mitochondrial electron transport chain. Pathway enrichment analyses also revealed the upregulation of neuroinflammation (including Toll-like receptor, TNF, and NFκB signaling) and phagocytosis, and the downregulation of mitochondrial oxidative phosphorylation, lysosomal acidification, and ubiquitin-proteasome pathways. Our findings suggest that neuroinflammation and a failure in both neuronal energy metabolism and protein degradation systems are consistent features underlying neurodegenerative diseases, despite differences in the extent of neuronal loss and brain regions involved.

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Cited by

Sorted by citations

Authors
Noori, A., Mezlini, A. M., Hyman, B. T., Serrano-Pozo, A., & Das, S.
Affiliations
Harvard University (US)
Corresponding author
Das, Sudeshna
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2021-02
Volume
149
Pages
105225
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2020.105225
PMC
PMC7856076
OpenAlex
W3116928997
Cited by
98
References
7
Citations by year
2026: 19 · 2025: 10 · 2024: 16 · 2023: 16 · 2022: 20 · 2021: 17
FWCI
1.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, other-oa)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Massachusetts Life Sciences Center
  • National Institute on Aging
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
neurodegeneration, Alzheimer's disease, Lewy body disease, amyotrophic lateral sclerosis, frontotemporal dementia, neuroinflammation, neuronal energy metabolism, proteostasis, protein aggregation, mitochondrial oxidative phosphorylation, ubiquitin-proteasome system, lysosomal acidification, innate immunity, phagocytosis, gene expression signatures
MeSH terms
Proteostasis, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Brain, Energy Metabolism, Humans, Inflammation, Inflammation Mediators, Neurodegenerative Diseases, Lewy Body Disease, Frontotemporal Dementia, Transcriptome

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