Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis

Roussarie, Jean-Pierre; Yao, Victoria; Rodriguez-Rodriguez, Patricia; Oughtred, Rose; Rust, Jennifer; Plautz, Zakary; Kasturia, Shirin; Albornoz, Christian A.; Wang, Wei; Schmidt, Eric F.; Dannenfelser, Ruth; Tadych, Alicja; Brichta, Lars; Barnea-Cramer, Alona; Heintz, Nathaniel; Hof, Patrick R.; Heiman, Myriam; Dolinski, Kara; Flajolet, Marc; Troyanskaya, Olga G.; Greengard, Paul

doi:10.1016/j.neuron.2020.06.010

Cited by 132 publications

(116 citation statements)

References 123 publications

(146 reference statements)

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“…5C) as described above. All three marks exhibit differential levels of expression within the cell types which can be in agreement with previous findings of selective cellular vulnerability in the neurodegenerative process [36] since above described chromatin marks regulates different cellular processes, where an array of the cellular processes was affected in a particular cell compared to neighboring cells as demonstrated recently in AD [102].…”

Section: Resultssupporting

confidence: 91%

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

Natarajan

Eisfeldt

Hammond

et al. 2020

Preprint

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We identified an individual with reduced penetrance (RedPenMC) associated with an autosomal dominant progranulin (GRN) pathogenic variant (p.Tyr294*) causing frontotemporal dementia. The RedPenMC carrier had no signs or symptoms of frontotemporal lobar degeneration in life or at autopsy. This resistance to develop expected pathology gives a unique opportunity to interrogate neurodegenerative mechanisms, identify protective disease modifiers, and gain new therapeutic insights. We performed multimodal droplet-based single nuclei analyses of the frontal cortex from the RedPenMC post-mortem, including unbiased transcriptomics and profiling of global levels of twelve chromatin marks. Further, we analyzed neurons directly reprogrammed from skin fibroblasts from RedPenMC. Single nuclei analyses revealed that the RedPenMC carrier showed a higher expression of GRN in microglia than in any other cell types as well as compared to an affected mutation carrier and a non-carrier. Global levels of heterochromatin marks H3k9me1 and H3k9me3 were significantly lower in the RedPenMC carrier, whereas global levels of H2A2 were significantly upregulated in the RedPenMC carrier compared to an affected mutation carrier. Analyses of directly reprogrammed neurons from the RedPenMC carrier suggested a dendritic loss of GRN and spillage of TAR DNA-binding protein 43 (TDP-43) from the nucleus into the cytoplasm which was not observed in directly reprogrammed neurons from non-carriers. Taken together, our data suggest that higher expression of GRN in microglia and reduced levels of repressive marks may provide endogenous protection against the disease process/neurodegeneration in the RedPenMC carrier. Our study uses unique patient material and provides novel insights into disease mechanisms that can be explored for designing new therapeutic approaches for GRN associated frontotemporal dementia.

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Section: Resultssupporting

confidence: 91%

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

Natarajan

Eisfeldt

Hammond

et al. 2020

Preprint

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“…BioGRID will continue to maintain existing data collections and to improve curation throughput by textmining approaches. New themed curation projects underway include Alzheimer's disease, 70 as well as new viral, bacterial and protozoan pathogens, all of which will be supported by dedicated themed project pages. Chemical-protein interaction datasets will be expanded by de novo curation and key partnerships with chemical and drug databases.…”

Section: Discussionmentioning

confidence: 99%

“…BioGRID interaction data and CRISPR screen data will continue to be openly disseminated through NCBI, UniProt and other meta‐databases, and we will continue to collaborate on interaction curation and dissemination with the major MODs and their unified resource, the Genome Alliance (http://www.alliancegenome.org). 71 All data in BioGRID and ORCS will be maintained with regular updates and made freely available without restriction. BioGRID curation projects will thus continue to serve both the academic biomedical research community and the commercial drug discovery sector.…”

Section: Discussionmentioning

confidence: 99%

The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions

et al. 2020

Self Cite

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The BioGRID (Biological General Repository for Interaction Datasets, http://thebiogrid.org) is an open‐access database resource that houses manually curated protein and genetic interactions from multiple species including yeast, worm, fly, mouse, and human. The ~1.93 million curated interactions in BioGRID can be used to build complex networks to facilitate biomedical discoveries, particularly as related to human health and disease. All BioGRID content is curated from primary experimental evidence in the biomedical literature, and includes both focused low‐throughput studies and large high‐throughput datasets. BioGRID also captures protein post‐translational modifications and protein or gene interactions with bioactive small molecules including many known drugs. A built‐in network visualization tool combines all annotations and allows users to generate network graphs of protein, genetic and chemical interactions. In addition to general curation across species, BioGRID undertakes themed curation projects in specific aspects of cellular regulation, for example the ubiquitin‐proteasome system, as well as specific disease areas, such as for the SARS‐CoV‐2 virus that causes COVID‐19 severe acute respiratory syndrome. A recent extension of BioGRID, named the Open Repository of CRISPR Screens (ORCS, http://orcs.thebiogrid.org), captures single mutant phenotypes and genetic interactions from published high throughput genome‐wide CRISPR/Cas9‐based genetic screens. BioGRID‐ORCS contains datasets for over 1,042 CRISPR screens carried out to date in human, mouse and fly cell lines. The biomedical research community can freely access all BioGRID data through the web interface, standardized file downloads, or via model organism databases and partner meta‐databases.

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“…In addition, neurons particularly sensitive to degeneration could have increased energy requirements, leading to increased sensitivity to mitochondrial stressors 141 , 149 . In this regard, neurons exhibiting functional plasticity might be more sensitive to degeneration than others 150 because continuous retraction and regrowth of synapses could increase demand for ATP.…”

Section: Differential Sensitivity Of Various Cell Types To Degenerationmentioning

confidence: 99%

A transition to degeneration triggered by oxidative stress in degenerative disorders

Stern

McNew

2020

Mol Psychiatry

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Although the activities of many signaling pathways are dysregulated during the progression of neurodegenerative and muscle degeneration disorders, the precise sequence of cellular events leading to degeneration have not been fully elucidated. Two kinases of particular interest, the growth-promoting Tor kinase and the energy sensor AMPK, appear to show reciprocal changes in activity during degeneration, with increased Tor activity and decreased AMPK activity reported. These changes in activity have been predicted to cause degeneration by attenuating autophagy, leading to accumulation of unfolded protein aggregates and dysfunctional mitochondria, the consequent increased production of reactive oxygen species (ROS), and ultimately oxidative damage. Here we propose that this increased ROS production not only causes oxidative damage but also ultimately induces an oxidative stress response that reactivates the redox-sensitive AMPK and activates the redox-sensitive stress kinase JNK. Activation of these kinases re-activates autophagy. Because at this late stage, cells have become filled with dysfunctional mitochondria and protein aggregates, which are autophagy targets, this autophagy reactivation induces degeneration. The mechanism proposed here emphasizes that the process of degeneration is dynamic, that dysregulated signaling pathways change over time and can transition from deleterious to beneficial and vice versa as degeneration progresses.

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Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis

Cited by 132 publications

References 123 publications

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions

A transition to degeneration triggered by oxidative stress in degenerative disorders

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