Intermediate Filaments in Neurodegenerative Diseases

Perrot, Rodolphe; Eyer, Joël

doi:10.5772/54676

Cited by 5 publications

(4 citation statements)

References 171 publications

(179 reference statements)

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“…Further, four genes encoding intermediate filaments, such as NES (nestin), are clustered together. They are primarily responsible for cell adhesion [30]. Furthermore, a cluster of three genes from the solute carrier family was found ( SLC3A2, SLC7A5 , and SLC7A6 ).…”

Section: Resultsmentioning

confidence: 99%

Statistical integration of multi-omics and drug screening data from cell lines

Bouhaddani

Höllerhage

et al. 2022

Preprint

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Parkinson's disease and multiple system atrophy are characterized by aggregation of the alpha-synuclein protein in the brain. The causes and consequences of this aggregation are currently unclear, hampering the development of an effective therapy against these synucleinopathies. To gain understanding in the neurobiological events underlying alpha-synuclein aggregation, LUHMES cell lines have been utilized to measure transcriptomics and proteomics data and perform differential regulation analyses. The LUHMES cells have also been used to screen 1600 FDA-approved drugs for their ability to reduce alpha-synuclein-induced toxicity. We implemented a probabilistic data integration method, POPLS-DA, to model alpha-synuclein overexpression in terms of the transcriptomics and proteomics data jointly. Using POPLS-DA, we selected 200 relevant genes and proteins and integrated this gene list with the FDA drugs that were validated to be protective against alpha-synuclein-induced toxicity. Using interactome and functional enrichment analyses, we identified clusters of synaptic and lysosome-related genes and proteins that were targeted by the protective drugs. We found that HSPA5, a member of the heat shock protein 70 family, was one of the most targeted genes by the validated drugs. Our integrative approach results provide new directions for therapeutic targets for synucleinopathies.

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Section: Resultsmentioning

confidence: 99%

Statistical integration of multi-omics and drug screening data from cell lines

Bouhaddani

Höllerhage

et al. 2022

Preprint

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“…Further, four genes encoding intermediate filaments, such as NES (nestin), are clustered together. They are primarily responsible for cell adhesion [17]. Furthermore, a cluster of three genes from the solute carrier family was found (SLC3A2, SLC7A5, and SLC7A6).…”

Section: Plos Computational Biologymentioning

confidence: 99%

Statistical integration of multi-omics and drug screening data from cell lines

el Bouhaddani,

Höllerhage,

et al. 2024

PLoS Comput Biol

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Data integration methods are used to obtain a unified summary of multiple datasets. For multi-modal data, we propose a computational workflow to jointly analyze datasets from cell lines. The workflow comprises a novel probabilistic data integration method, named POPLS-DA, for multi-omics data. The workflow is motivated by a study on synucleinopathies where transcriptomics, proteomics, and drug screening data are measured in affected LUHMES cell lines and controls. The aim is to highlight potentially druggable pathways and genes involved in synucleinopathies. First, POPLS-DA is used to prioritize genes and proteins that best distinguish cases and controls. For these genes, an integrated interaction network is constructed where the drug screen data is incorporated to highlight druggable genes and pathways in the network. Finally, sfunctional enrichment analyses are performed to identify clusters of synaptic and lysosome-related genes and proteins targeted by the protective drugs. POPLS-DA is compared to other single- and multi-omics approaches. We found that HSPA5, a member of the heat shock protein 70 family, was one of the most targeted genes by the validated drugs, in particular by AT1-blockers. HSPA5 and AT1-blockers have been previously linked to α-synuclein pathology and Parkinson’s disease, showing the relevance of our findings. Our computational workflow identified new directions for therapeutic targets for synucleinopathies. POPLS-DA provided a larger interpretable gene set than other single- and multi-omic approaches. An implementation based on R and markdown is freely available online.

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“… 2012 ). Neuronal aggregation is a general characteristic found in many neurodegenerative diseases, such as neuronal intermediate filament inclusion disease (NIFID), amyotrophic lateral sclerosis (ALS), Alzheimer’s diseases, Parkinson’s disease, and Huntington’s disease (Ross and Poirier 2004 ; Ching and Liem 2006 ; Perrot and Eyer 2013 ). Hence, we intended to test whether EPO secreted by EPO-overexpressing NIH/3T3 fibroblasts enhances the survival of degenerating PC12-INT-EGFP cells.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin produced by genetic‐modified NIH/3T3 fibroblasts enhances the survival of degenerating neurons

Chen

Chien

2015

Brain and Behavior

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BackgroundErythropoietin (EPO) has potent neuroprotective effects. The short-term delivery of high-dose EPO seemed to improve patients’ neuromuscular functions; however, excessive EPO resulted in systematically high hematocrit and thrombotic risk. In our study, we established a cellular material for future in vivo studies of neurodegenerative diseases based on EPO provided regionally at a nontoxic level.MethodsA mouse EPO cDNA was subcloned into the pCMS-EGFP vector and transfected into NIH/3T3 fibroblasts to design a biological provider that can regionally release EPO for the treatment of neurological diseases. After G418 selection, a stable EPO-overexpressing cell line, EPO-3T3-EGFP, was established. To further confirm the neuroprotective abilities of secreted EPO from EPO-3T3-EGFP cells, a cell model of neurodegeneration, PC12-INT-EGFP, was applied.ResultsThe expression level of EPO was highly elevated in EPO-3T3-EGFP cells, and an abundant amount of EPO secreted from EPO-3T3-EGFP cells was detected in the extracellular milieu. After supplementation with conditioned medium prepared from EPO-3T3-EGFP cells, the survival rate of PC12-INT-EGFP cells was significantly enhanced. Surprisingly, a fraction of aggregated cytoskeletal EGFP-tagged α-internexin in PC12-INT-EGFP cells was disaggregated and transported into neurites dynamically. The immunocytochemical distribution of IF proteins, including NF-M, phosphorylated-NF-M, and the α-INT-EGFP fusion protein, were less aggregated in the perikaryal region and transported into neurites after the EPO treatment.ConclusionThe established EPO-overexpressing NIH/3T3 cell line, EPO-3T3-EGFP, may provide a material for future studies of cell-based therapies for neurodegenerative diseases via the secretion of EPO on a short-term, high-dose, regional basis.

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Intermediate Filaments in Neurodegenerative Diseases

Cited by 5 publications

References 171 publications

Statistical integration of multi-omics and drug screening data from cell lines

Statistical integration of multi-omics and drug screening data from cell lines

Statistical integration of multi-omics and drug screening data from cell lines

Erythropoietin produced by genetic‐modified NIH/3T3 fibroblasts enhances the survival of degenerating neurons

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