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

NEUROBIOLOGY OF DISEASE

卷:149

Review

Noori, Ayush^1,2,3,4  Mezlini, Aziz M.^2,3,4,5  Hyman, Bradley T.^2,4,5  Serrano-Pozo, Alberto^2,4,5  Das, Sudeshna^2,3,4,5 

[1] Harvard Univ, Cambridge, MA 02138 USA

[2] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[3] MIND Data Sci Lab, Cambridge, MA 02139 USA

[4] MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA

[5] Harvard Med Sch, Boston, MA 02115 USA

关键词: Alzheimer's disease;    Amyotrophic lateral sclerosis;    Frontotemporal dementia;    Lewy body diseases;    Meta-analysis;    Mitochondrial energy metabolism;    Neurodegeneration;    Neuroinflammation;    Proteostasis;    Transcriptomics;   

DOI  :  10.1016/j.nbd.2020.105225

来源: Elsevier

【 摘 要 】

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 ALSFTD 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 NF kappa B 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.