Transcriptome and proteome profiling of neural stem cells from the human subventricular zone in Parkinson’s disease

Abstract

It is currently accepted that the human brain has a limited neurogenic capacity and an impaired regenerative potential. We have previously shown the existence of CD271-expressing neural stem cells (NSCs) in the subventricular zone (SVZ) of Parkinson’s disease (PD) patients, which proliferate and differentiate towards neurons and glial cells in vitro. To study the molecular profile of these NSCs in detail, we performed RNA sequencing and mass spectrometry on CD271 + NSCs isolated from human post-mortem SVZ and on homogenates of the SVZ. CD271 + cells were isolated through magnetic cell separation (MACS). We first compared the molecular profile of CD271 + NSCs to the SVZ homogenate from control donors and then compared CD271 + cells to CD11b + microglia. These results confirmed their neural stem cell identity. Finally we compared controls and PD patients to establish a specific molecular profile of NSCs and the SVZ in PD. While our transcriptome analysis did not identify any differentially expressed genes in the SVZ between control and PD patients, our proteome analysis revealed several proteins that were differentially expressed in PD. Some of these proteins are involved in cytoskeletal organization and mitochondrial function. Transcriptome and proteome analyses of NSCs from PD revealed changes in the expression of genes and proteins involved in metabolism, transcriptional activity and cytoskeletal organization. Our data suggest that NSCs may transit into a primed-quiescent state, that is in an “alert” non-proliferative phase in PD. Our results not only confirm pathological hallmarks of PD (e.g. impaired mitochondrial function), but also show that the NSCs from SVZ undergo significant changes at both transcriptome and proteome level following PD. Electronic supplementary material The online version of this article (10.1186/s40478-019-0736-0) contains supplementary material, which is available to authorized users.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…NSCs, which are GFAP (δ isoform) and nerve growth factor receptor (NGFR, a.k.a. CD271) positive, were shown to proliferate and differentiate towards neurons and glial cells in vitro, then supporting the potential ability to stimulate these NSCs to regenerate the injured brain (van den Berge et al, ; Donega et al, ). In post‐mortem PD brains a deregulation of SVZ neurogenesis was revealed, with decreased NSC proliferation correlated with the progression of PD, while L‐DOPA treatment appeared to increase NSC numbers.…”

“…NSCs have been identified in the SVZ of the aged human brain (Apple et al, 2017;Berge et al, 2011;Bergman, Spalding, & Frisén, 2015;Donega et al, 2019;Leonard et al, 2009;Radad et al, 2017;van den Berge et al, 2010;Wang et al, 2012;Winner, Vogt-Weisenhorn, et al, 2009b). NSCs, which are GFAP (δ isoform) and nerve growth factor receptor (NGFR, a.k.a.…”

Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

“…Thus, precise phenotyping measures are required to identify neurogenic from non-neurogenic astrocytes. Some studies suggest that human NSCs populations persist and contribute to neurogenesis throughout adulthood [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. Others have detected significant reductions during childhood, ranging from simply lower activity all the way to negligible or nonexistent in adults [ 81 , 82 , 83 , 84 ].…”

Insights Into Translatomics in the Nervous System

“…Indeed, various neurological diseases, including neuropathic pain ( Colloca et al, 2017 ), neurodegenerative disorder ( Poewe et al, 2017 ), multiple sclerosis ( Filippi et al, 2018 ), fragile X syndrome (FXS) ( Hagerman et al, 2017 ) depression ( Aguilar-Valles et al, 2018 ) result from aberrant translation. Multiple studies have evaluated gene expression changes caused by external stimuli ( Floriou-Servou et al, 2018 ) and neurological disorders ( Shawahna et al, 2011 ; Donega et al, 2019 ) combining transcriptomic and proteomic profiling. However, their resolution is limited by high cellular heterogeneity ( Sharma et al, 2015 ), alternative splicing ( Su et al, 2018 ), translational regulation ( Shigeoka et al, 2016 ), protein degradation ( Daniele et al, 2018 ), and protein localization ( Holt et al, 2019 ) likely causing the poor correlation seen between mRNAs and protein levels in the nervous system.…”