Brain transcriptomic profiling reveals common alterations across neurodegenerative and psychiatric disorders

Sadeghi, Iman; Gispert, Juan Domingo; Palumbo, Emilio; Muñoz-Aguirre, Manuel; Wucher, Valentin; D’Argenio, Valeria; Santpere, Gabriel; Navarro, Arcadi; Guigó, Roderic; Vilor‐Tejedor, Natàlia

doi:10.1016/j.csbj.2022.08.037

Cited by 13 publications

(6 citation statements)

References 133 publications

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“…PATL2, however, remains a poorly studied gene especially within the neurodegenerative diseases. Various meta-analyses on human https://doi.org/10.1038/s41531-024-00698-y transcriptome studying aging, Alzheimer's disease, as well as other neurodegenerative conditions (e.g., Huntington's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis), have not found a significant association between PATL2 expression levels and disease risk [63][64][65] . The role of PATL2 in immune cells remains unclear, other than being upregulated in lymphocytes with increasing age.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic imputation of genetic risk variants uncovers novel whole-blood biomarkers of Parkinson’s disease

Chew,

Mai,

Ouyang

et al. 2024

npj Parkinsons Dis.

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Blood-based gene expression signatures could potentially be used as biomarkers for PD. However, it is unclear whether genetically-regulated transcriptomic signatures can provide novel gene candidates for use as PD biomarkers. We leveraged on the Genotype-Tissue Expression (GTEx) database to impute whole-blood transcriptomic expression using summary statistics of three large-scale PD GWAS. A random forest classifier was used with the consensus whole-blood imputed gene signature (IGS) to discriminate between cases and controls. Outcome measures included Area under the Curve (AUC) of Receiver Operating Characteristic (ROC) Curve. We demonstrated that the IGS (n = 37 genes) is conserved across PD GWAS studies and brain tissues. IGS discriminated between cases and controls in an independent whole-blood RNA-sequencing study (1176 PD, 254 prodromal, and 860 healthy controls) with mean AUC and accuracy of 64.8% and 69.4% for PD cohort, and 78.8% and 74% for prodromal cohort. PATL2 was the top-performing imputed gene in both PD and prodromal PD cohorts, whose classifier performance varied with biological sex (higher performance for males and females in the PD and prodromal PD, respectively). Single-cell RNA-sequencing studies (scRNA-seq) of healthy humans and PD patients found PATL2 to be enriched in terminal effector CD8+ and cytotoxic CD4+ cells, whose proportions are both increased in PD patients. We demonstrated the utility of GWAS transcriptomic imputation in identifying novel whole-blood transcriptomic signatures which could be leveraged upon for PD biomarker derivation. We identified PATL2 as a potential biomarker in both clinical and prodromic PD.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic imputation of genetic risk variants uncovers novel whole-blood biomarkers of Parkinson’s disease

Chew,

Mai,

Ouyang

et al. 2024

npj Parkinsons Dis.

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“…The failure to reproduce MSA filaments in vitro has suggested that oligodendroglial environment-derived factors may be essential not only in the initial misfolding but also in the templated amplification. 111 Diverse transcriptomic profiles have been reported between cell types and brain regions, [158][159][160] suggesting the involvement of genetic factors and their changes with aging in cell type-specific environments. However, there is a critical question to be resolved in considering the importance of the oligodendroglial environment for the formation of the MSA folds.…”

Section: Implications Of Conformational Differences Between Patient-a...mentioning

confidence: 99%

Ultrastructures of α-Synuclein Filaments in Synucleinopathy Brains and Experimental Models

Tarutani,

Hasegawa

2024

JMD

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Intracellular α-synuclein (α-syn) inclusions are a neuropathological hallmark of Lewy body disease (LBD) and multiple system atrophy (MSA), both of which are termed synucleinopathies. LBD is defined by Lewy bodies and Lewy neurites in neurons, while MSA displays glial cytoplasmic inclusions in oligodendrocytes. Pathological α-syn adopts an ordered filamentous structure with a 5–10 nm filament diameter, and this conformational change has been suggested to be involved in the disease onset and progression. Synucleinopathies also exhibit characteristic ultrastructural and biochemical properties of α-syn filaments, and α-syn strains with distinct conformations have been identified. Numerous experimental studies have supported the idea that pathological α-syn self-amplifies and spreads throughout the brain, during which processes the conformation of α-syn filaments may drive the disease specificity. In this review, we summarize the ultrastructural features and heterogeneity of α-syn filaments in the brains of patients with synucleinopathy and in experimental models of seeded α-syn aggregation.

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“…RNA sequence analyses allow one to evaluate gene expression and identify mechanisms that may be involved in their regulation; as a consequence, NGS has been widely used in this context [47][48][49]. However, although NGS platforms have the advantage of sequencing at competitive costs and with a great sequencing depth, these methodologies have some limitations in RNA sequencing applications [50].…”

Section: Rna Sequencingmentioning

confidence: 99%

The Third-Generation Sequencing Challenge: Novel Insights for the Omic Sciences

Scarano,

Veneruso,

De Simone

et al. 2024

Biomolecules

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The understanding of the human genome has been greatly improved by the advent of next-generation sequencing technologies (NGS). Despite the undeniable advantages responsible for their widespread diffusion, these methods have some constraints, mainly related to short read length and the need for PCR amplification. As a consequence, long-read sequencers, called third-generation sequencing (TGS), have been developed, promising to overcome NGS. Starting from the first prototype, TGS has progressively ameliorated its chemistries by improving both read length and base-calling accuracy, as well as simultaneously reducing the costs/base. Based on these premises, TGS is showing its potential in many fields, including the analysis of difficult-to-sequence genomic regions, structural variations detection, RNA expression profiling, DNA methylation study, and metagenomic analyses. Protocol standardization and the development of easy-to-use pipelines for data analysis will enhance TGS use, also opening the way for their routine applications in diagnostic contexts.

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Brain transcriptomic profiling reveals common alterations across neurodegenerative and psychiatric disorders

Cited by 13 publications

References 133 publications

Transcriptomic imputation of genetic risk variants uncovers novel whole-blood biomarkers of Parkinson’s disease

Transcriptomic imputation of genetic risk variants uncovers novel whole-blood biomarkers of Parkinson’s disease

Ultrastructures of α-Synuclein Filaments in Synucleinopathy Brains and Experimental Models

The Third-Generation Sequencing Challenge: Novel Insights for the Omic Sciences

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