Cell-Type-Specific Gene Expression Profiling in Adult Mouse Brain Reveals Normal and Disease-State Signatures

Mérienne, Nicolas; Meunier, Cécile; Schneider, Anne T.; Séguin, Jonathan; Nair, Satish S.; Rocher, Anne B.; Gras, Stéphanie Le; Keime, Céline; Faull, Richard L.M.; Pellerin, Luc; Chatton, Jean–Yves; Néri, Christian; Mérienne, Karine; Déglon, Nicole

doi:10.1016/j.celrep.2019.02.003

Cited by 59 publications

(56 citation statements)

References 59 publications

(109 reference statements)

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“…Interestingly, previous studies demonstrated that lamin B1 over-expression in the central nervous system leads to epigenetic alterations affecting the heterochromatin protein 1 β(HP1β) and methylated histone H3 (K3H9) as well as transcriptional programs mostly linked to glial cells 16 . In agreement with that, regions with gained chromatin accessibility in our ATAC-seq data showed decreased levels of lamin B1, correlative increased expression and were enriched in terms associated with cell division and development, more typically associated to glial than to neuronal cells 50 . While a previous study showed a general gain of chromatin accessibility in HD T-cells 51 , our hippocampal ATAC-seq data showed a bi-directionality in chromatin accessibility changes, with a clear compaction of neuronal-associated regulatory regions and increased chromatin relaxation in developmental related ones.…”

Section: Discussionsupporting

confidence: 91%

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Alcalà-Vida

Garcia‐Forn

Creus-Muncunill

et al. 2020

Preprint

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Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing an involvement of increased lamin B1 levels in the pathophysiology of Huntington's disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging we demonstrate that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, which could contribute to transcriptional alterations we determined by RNA sequencing. Supporting lamin B1 alterations as a causal role in mutant-huntingtin mediated neurodegeneration, pharmacological normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work point out increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.Keywords: chromatin accessibility, LAD, R6/1 mouse, nuclear morphology, nuclear permeability of the polyglutamine chain at the amino terminus of the huntingtin (Htt) protein inducing selfassociation and aggregation. Consequently, mutant Htt (mHtt) loses its biological functions and becomes toxic 13 . In HD, medium-sized spiny neurons (MSNs), the GABAergic output projection neurons that account for the vast majority (90-95%) of all striatal neurons, are mainly affected. Although motor symptoms are the most prominent, psychiatric alterations and cognitive decline appear first in HD patients, which become more evident as the disease progresses. Cognitive deficits are related to the dysfunction of the corticostriatal pathway and the hippocampus and, together with motor deficits, have been replicated in most HD mouse models 14 .Molecular mechanisms leading to nuclear lamina alterations in neurons expressing mHtt remain to be elucidated. Previous results from our lab suggested that decreased levels of the pro-apoptotic kinase PKC would lead to an aberrant accumulation of lamin B 15 which, in turn, could have a significant influence in the nuclear lamina structure 16,17 . Therefore, here we sought to deeply characterize the impact of lamin alterations in HD brain at physiological (studying nuclear lamina morphology and nucleo-cytoplasmic transport), transcriptomic (by generating RNA-sequencing (RNA-seq) data) and epigenetic (analyzing lamin chromatin binding and chromatin accessibility) levels by using the R6/1 transgenic mouse model of HD and human post-mortem brain samples. ResultsLamin B levels are increased in a region-specific manner in HD brain. Lamin B1, B2, and A/C protein levels were analyzed in the striatum, cortex and hippocampus of wild-type and R6/1 mice, a transgenic mouse model of HD over-expressing the exon 1 of the human mutant huntingtin 18 , at different ages. Western blot a...

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Section: Discussionsupporting

confidence: 91%

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Alcalà-Vida

Garcia‐Forn

Creus-Muncunill

et al. 2020

Preprint

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“…This protein is important in hair and tooth development 24 , and levels of EDA2R have been shown to increase with age in blood 25 and lung tissue 26 . It was also associated with reactive astrogliosis in mice 27 and enriched in mouse astrocytes 28 , indicating that higher levels of this protein may reduce cognitive ability by reducing the number of healthy neurons. Other proteins that were relatively strongly associated with general fluid cognitive ability in the LBC1936 and the metaanalysis of the LBC1936 and INTERVAL-Old sample included sialoadhesin encoded by the SIGLEC1 gene on chromosome 20, a member of the immunoglobulin family 29 , which may influence cognitive ability through its roles in demyelination and neuroinflammation 30 ; poliovirus receptor encoded by the PVR gene on chromosome 19-viral infections have been previously linked to neurodegeneration 31 ; R-spondin-1 encoded by the RSPO1 gene on chromosome 1 and expressed in the central nervous system during development 32 ; discoidin domain receptor family, member 1 encoded by the DDR1 gene on chromosome 6, which is important in myelination 33 .…”

Section: Discussionmentioning

confidence: 99%

Neurology-related protein biomarkers are associated with cognitive ability and brain volume in older age

et al. 2020

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Identifying biological correlates of late life cognitive function is important if we are to ascertain biomarkers for, and develop treatments to help reduce, age-related cognitive decline. Here, we investigated the associations between plasma levels of 90 neurologyrelated proteins (Olink® Proteomics) and general fluid cognitive ability in the Lothian Birth Cohort 1936 (LBC1936, N = 798), Lothian Birth Cohort 1921 (LBC1921, N = 165), and the INTERVAL BioResource (N = 4451). In the LBC1936, 22 of the proteins were significantly associated with general fluid cognitive ability (β between −0.11 and −0.17). MRI-assessed total brain volume partially mediated the association between 10 of these proteins and general fluid cognitive ability. In an age-matched subsample of INTERVAL, effect sizes for the 22 proteins, although smaller, were all in the same direction as in LBC1936. Plasma levels of a number of neurology-related proteins are associated with general fluid cognitive ability in later life, mediated by brain volume in some cases.

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“…This protein is important in hair and tooth development 21 and levels of EDA2R have been shown to increase with age in blood 22 and lung tissue 23 . It was also associated with reactive astrogliosis in mice 24 and enriched in mouse astrocytes 25 . Other proteins that were relatively strongly associated with general fluid cognitive ability in the LBC1936 and the meta-analysis of the LBC1936 and INTERVAL-Old sample included sialoadhesion encoded by the SIGLEC1 gene on chromosome 20, a member of the immunoglobulin family 26 ; poliovirus receptor encoded by the PVR gene on chromosome 19; and R-spondin-1 encoded by the RSPO1 gene on chromosome 1.…”

Section: Discussionmentioning

confidence: 93%

Neurology-related protein biomarkers are associated with general fluid cognitive ability and brain volume in older age

Cox²,

Bell

et al. 2019

Preprint

View full text Add to dashboard Cite

Identifying the biological correlates of late life cognitive function is important if we are to ascertain biomarkers for, and develop treatments to help reduce, age-related cognitive decline. This study investigated the associations between plasma levels of 91 neurology-related proteins (Olink® Proteomics) and general fluid cognitive ability in the Lothian Birth Cohort 1936 (LBC1936, N=798), the Lothian Birth Cohort 1921 (LBC1921, N=165), and the INTERVAL BioResource, (N=4,451). In LBC1936, we also examined mediation of protein-cognitive ability associations by MRI-derived indices of brain structure. In the LBC1936, 22 of the proteins and the first principal component (PC) created from a PC analysis of the 91 proteins, were associated with general fluid cognitive ability (β between -0.11 and -0.17, p<0.0029).Total brain volume partially mediated the association between 10 of these proteins and general fluid cognitive ability. Effect sizes for the 22 proteins, although smaller, were all in the same direction as in LBC1936 in an age-matched subsample of INTERVAL. Similar effect sizes were found for the majority of these 22 proteins in the older LBC1921. The associations were not replicated in a younger subset of INTERVAL. In conclusion, we identified plasma levels of a number of neurology-related proteins that were associated with general fluid cognitive ability in later life, some of which were mediated by brain volume.

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Cell-Type-Specific Gene Expression Profiling in Adult Mouse Brain Reveals Normal and Disease-State Signatures

Cited by 59 publications

References 59 publications

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Neurology-related protein biomarkers are associated with cognitive ability and brain volume in older age

Neurology-related protein biomarkers are associated with general fluid cognitive ability and brain volume in older age

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