A5063774739- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Mitochondrial Function and Pathology
- Plant Molecular Biology Research
- Signaling Pathways in Disease
- Microtubule and mitosis dynamics
- Cellular transport and secretion
- Bipolar Disorder and Treatment
- Receptor Mechanisms and Signaling
- PI3K/AKT/mTOR signaling in cancer
- Genetics and Neurodevelopmental Disorders
- Cardiomyopathy and Myosin Studies
- Neurological diseases and metabolism
- NF-κB Signaling Pathways
- Nuclear Receptors and Signaling
- Cancer, Hypoxia, and Metabolism
- Insect Resistance and Genetics
- Protein Structure and Dynamics
- Heat shock proteins research
- Epigenetics and DNA Methylation
- RNA regulation and disease
- Alzheimer's disease research and treatments
- Genomics and Chromatin Dynamics
Daegu Gyeongbuk Institute of Science and Technology
2016-2024
Broad Institute
2024
Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes (Akap11, Dagla, Gria3, Grin2a, Sp4, Srrm2, Zmym2). While all studied regions were affected, the striatum and thalamus emerged as key of convergence. Striatum showed downregulation synapse- oxidative phosphorylation-related gene...
Dendrite aberration is a common feature of neurodegenerative diseases caused by protein toxicity, but the underlying mechanisms remain largely elusive. Here, we show that nuclear polyglutamine (polyQ) toxicity resulted in defective terminal dendrite elongation accompanied loss Golgi outposts (GOPs) and decreased supply plasma membrane (PM) Drosophila class IV dendritic arborization (da) (C4 da) neurons. mRNA sequencing revealed genes downregulated polyQ proteins included many secretory...
Significance It remains unclear how the structural properties of polyglutamine (polyQ) proteins, which underlie several neurodegenerative disorders, including Huntington’s disease and spinocerebellar ataxias (SCAs), translate into toxicity these proteins. Here, we demonstrate that coiled-coil structures in expanded polyQ regions SCA type 3 (SCA3) proteins cause dendrite defects Drosophila neurons, as well behavioral abnormalities. Moreover, interactions SCA3 with Foxo mediated by domains two...
Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. We conducted multi-omic analyses Akap11 mutant mouse brains report neurobiological functions consequences its absence. interacts with multiple proteins involved signaling proteostasis. In Akap11+/- Akap11-/- synapses, PKA levels were markedly elevated, many synaptic hyperphosphorylated at substrate sites. showed extensive transcriptomic changes,...
Abstract Rare loss-of-function (LoF) variants in SRRM2 , which encodes the splicing factor, are associated with schizophrenia and a neurodevelopmental disorder. How haploinsufficiency of leads to brain dysfunction is unknown. We find that Srrm2 +/- mice display (i) large-scale changes gene expression neuronal glial cells, affecting synapse-related other common molecular pathways across multiple regions, (ii) reduction key postsynaptic proteins, including gamma isoform SynGAP, itself encoded...
Dendrite pathology is frequently observed in various neurodegenerative diseases (NDs). Although previous studies identified several pathogenic mediators of dendrite defects that act through loss function NDs, the underlying mechanisms remain largely unexplored. Here, our search for additional contributors to NDs identifies Relish/NF-κB as a novel gain-of-toxicity–based mediator animal models polyglutamine (polyQ) and amyotrophic lateral sclerosis (ALS). In Drosophila model polyQ diseases,...
Abstract Accumulating evidence hints heterochromatin anchoring to the inner nuclear membrane as an upstream regulatory process of gene expression. Given that formation neural progenitor cell lineages and subsequent maintenance postmitotic neuronal identity critically rely on transcriptional regulation, it seems possible development cells is influenced by type-specific and/or context-dependent programmed regulation anchoring. Here, we explored this possibility genetically disrupting...
Abstract Schizophrenia and bipolar disorder are highly heritable mental illnesses with unclear pathophysiology. Heterozygous loss-of-function mutations of Sp4 , a zinc-finger transcription factor, greatly increase risk schizophrenia disorder. To investigate the molecular functions in an unbiased manner vivo we performed multi-omics analyses mutant mice. Bulk single nucleus RNA-seq data showed prominent gene expression changes all brain regions most cell types, including neuronal non-neuronal...
Accumulating evidence hints heterochromatin anchoring to inner nuclear membrane as an upstream regulatory process of gene expression. Given that formation neural progenitor cell lineages and subsequent maintenance postmitotic neuronal identity critically rely on the transcriptional regulation, it seems possible development cells is influenced by type-specifically and/or context-dependently programmed control its status. Here, we explored this possibility genetically perturbing evolutionarily...