Biology subjects

Gentleman, S.

Publications and source records attributed to Gentleman, S..

3 recordsLinked to original sources

bioRxiv2022

Common signatures of differential microRNA expression in Parkinson's and Alzheimer's disease brains

BackgroundDysregulation of microRNA (miRNA)-mediated gene expression has been implicated in the pathogenesis and course of many neurodegenerative diseases including Parkinsons disease (PD). However, the functionally relevant miRNAs remain largely unknown. Previous meta-analyses on differential miRNA expression data in post-mortem PD brains have highlighted several miRNAs showing consistent and statistically significant effects. However, these meta-analyses were based on exceedingly small sample sizes. MethodsIn this study, we quantified the expression of the four most compelling PD candidate miRNAs from these meta-analyses in the superior temporal gyrus (STG) of one of the largest case-control post-mortem brain datasets available (261 samples), thereby quadruplicating previously investigated sample sizes. Furthermore, we probed for common differential miRNA expression signatures with Alzheimers disease (AD) by also analyzing these miRNAs in post-mortem STG of 190 AD patients and controls and by testing six top AD miRNAs in the PD brains. ResultsOf all ten analyzed miRNAs, PD candidate miRNA homo sapiens (hsa-) miR-132-3p showed evidence for differential expression in both PD (p=4.89E-06) and AD (p=3.20E-24), and AD miRNAs hsa-miR-132-5p (p=4.52E-06) and hsa-miR-129-5p (p=0.0379) showed evidence for differential expression in PD. Combining these novel data with previously published data substantially improved the statistical support (=3.85E-03 using Bonferroni correction) of the corresponding meta-analyses clearly and compellingly implicating these miRNAs in both PD and AD. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with neuropathological Braak PD staging (p=3.51E-03/p=0.0117), suggesting that these miRNAs may play a role in -synuclein aggregation beyond the early disease phase. ConclusionsOur study represents the largest independent assessment of recently highlighted candidate brain miRNAs in PD and AD post-mortem brain samples, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both PD and AD brains, potentially pinpointing shared pathogenic mechanisms across these neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology

To better define roles that astrocytes and microglia play in Alzheimers disease (AD), we used single-nuclei RNA sequencing to comprehensively characterize transcriptomes in astrocyte and microglia nuclei isolated post mortem from neuropathologically-defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid and pTau expression. Astrocytes were enriched for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, proteostasis and autophagy were highly enriched in microglia and perivascular macrophages. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

neuroscience↗

bioRxiv2021

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

Parkinsons disease (PD), Parkinsons 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.

neuroscience↗