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4 results on '"Kara Heeren"'

1. Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response

Author

Christine Germeys, Tijs Vandoorne, Kristofer Davie, Suresh Poovathingal, Kara Heeren, Wendy Vermeire, FatemehArefeh Nami, Matthieu Moisse, Annelies Quaegebeur, Annerieke Sierksma, Laura Rué, Adrià Sicart, Caroline Eykens, Lenja De Cock, Bart De Strooper, Peter Carmeliet, Philip Van Damme, Katrien De Bock, and Ludo Van Den Bosch

Subjects
CP: Neuroscience, Biology (General), QH301-705.5
Abstract

Summary: Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.

Published
2024
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2. Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS

Author

Janani Parameswaran, Nancy Zhang, Elke Braems, Kedamawit Tilahun, Devesh C Pant, Keena Yin, Seneshaw Asress, Kara Heeren, Anwesha Banerjee, Emma Davis, Samantha L Schwartz, Graeme L Conn, Gary J Bassell, Ludo Van Den Bosch, and Jie Jiang

Subjects
C9ORF72, PKR, antisense RNA, FTD/ALS, integrated stress response, Medicine, Science, Biology (General), QH301-705.5
Abstract

GGGGCC (G4C2) hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C4G2) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9ORF72 antisense C4G2 repeat expanded RNAs trigger the activation of the PKR/eIF2α-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG-initiated translation, leading to global translation inhibition and stress granule formation. Reducing PKR levels with either siRNA or morpholinos mitigates integrated stress response and toxicity caused by the antisense C4G2 RNAs in cell lines, primary neurons, and zebrafish. Increased phosphorylation of PKR/eIF2α is also observed in the frontal cortex of C9ORF72 FTD/ALS patients. Finally, only antisense C4G2, but not sense G4C2, repeat expanded RNAs robustly activate the PKR/eIF2α pathway and induce aberrant stress granule formation. These results provide a mechanism by which antisense C4G2 repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9ORF72 repeat expansions.

Published
2023
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4. HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS

Author

Elke Braems, Valérie Bercier, Evelien Van Schoor, Kara Heeren, Jimmy Beckers, Laura Fumagalli, Lieselot Dedeene, Matthieu Moisse, Ilse Geudens, Nicole Hersmus, Arpan R. Mehta, Bhuvaneish T. Selvaraj, Siddharthan Chandran, Ritchie Ho, Dietmar R. Thal, Philip Van Damme, Bart Swinnen, and Ludo Van Den Bosch

Subjects
EXPRESSION, Clinical Neurology, AMYOTROPHIC-LATERAL-SCLEROSIS, Pathology and Forensic Medicine, Heterogeneous-Nuclear Ribonucleoprotein K, Cellular and Molecular Neuroscience, Pick Disease of the Brain, C9orf72, BINDING, Pathology, Animals, RNA, Antisense, PHOSPHORYLATION, Zebrafish, RIBONUCLEOTIDE REDUCTASE M2, P53, DNA Repeat Expansion, Science & Technology, HEXANUCLEOTIDE REPEAT, C9orf72 Protein, HNRNPK, Amyotrophic Lateral Sclerosis, Neurosciences, NEURODEGENERATION, RNA toxicity, REPEAT EXPANSION, Frontotemporal Dementia, RRM2, RNA, DNA damage, MOTOR-NEURONS, Neurology (clinical), Neurosciences & Neurology, ALS, Life Sciences & Biomedicine, DNA Damage
Abstract

A ‘GGGGCC’ repeat expansion in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The exact mechanism resulting in these neurodegenerative diseases remains elusive, but C9 repeat RNA toxicity has been implicated as a gain-of-function mechanism. Our aim was to use a zebrafish model for C9orf72 RNA toxicity to identify modifiers of the ALS-linked phenotype. We discovered that the RNA-binding protein heterogeneous nuclear ribonucleoprotein K (HNRNPK) reverses the toxicity of both sense and antisense repeat RNA, which is dependent on its subcellular localization and RNA recognition, and not on C9orf72 repeat RNA binding. We observed HNRNPK cytoplasmic mislocalization in C9orf72 ALS patient fibroblasts, induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem motor cortex and spinal cord, in line with a disrupted HNRNPK function in C9orf72 ALS. In C9orf72 ALS/FTD patient tissue, we discovered an increased nuclear translocation, but reduced expression of ribonucleotide reductase regulatory subunit M2 (RRM2), a downstream target of HNRNPK involved in the DNA damage response. Last but not least, we showed that increasing the expression of HNRNPK or RRM2 was sufficient to mitigate DNA damage in our C9orf72 RNA toxicity zebrafish model. Overall, our study strengthens the relevance of RNA toxicity as a pathogenic mechanism in C9orf72 ALS and demonstrates its link with an aberrant DNA damage response, opening novel therapeutic avenues for C9orf72 ALS/FTD.

Published
2022

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