A5033978210- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Genetic Neurodegenerative Diseases
- RNA and protein synthesis mechanisms
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Cancer-related gene regulation
- Biocrusts and Microbial Ecology
- Biotin and Related Studies
- Food Industry and Aquatic Biology
- Alzheimer's disease research and treatments
- Physiological and biochemical adaptations
- Fungal and yeast genetics research
- Protein Structure and Dynamics
- Advanced Proteomics Techniques and Applications
- Seed Germination and Physiology
- Neurological diseases and metabolism
- Neuroscience and Neuropharmacology Research
- Microtubule and mitosis dynamics
- Advanced Fluorescence Microscopy Techniques
- Hepatitis Viruses Studies and Epidemiology
- thermodynamics and calorimetric analyses
- Cellular transport and secretion
Neurological Research Institute
2023-2025
Texas Children's Hospital
2023-2025
Baylor College of Medicine
2023-2025
Children's Cancer Center
2023-2025
Stanford University
2017-2023
KU Leuven
2012-2020
VIB-KU Leuven Center for Brain & Disease Research
2015-2020
Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation multiple membrane-less organelles involved RNA metabolism, including stress granules. Defects granule homeostasis constitute a cornerstone ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for ALS-linked proteins. We now identify active arginine-rich domains these separations. Moreover, dipeptide repeats (DPRs) derived from...
Phase separation of multivalent protein and RNA molecules underlies the biogenesis biomolecular condensates such as membraneless organelles. In vivo, these encompass hundreds distinct types that typically organize into multilayered structures supporting differential partitioning regions with material properties. The interplay between driven (active) versus spontaneous (passive) processes are required for enabling formation coexisting layers properties remains unclear. Here, we deploy...
Abstract Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation these repeats produces dipeptide proteins (DPRs) that may neurodegeneration. We performed a modifier screen Drosophila discovered critical role for importins exportins, Ran-GTP cycle regulators, nuclear pore components arginine methylases mediating DPR toxicity. These findings provide evidence an...
Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. It remains incompletely resolved how biological function encoded these assemblies whether this depends on their material state. The conserved intrinsically disordered protein PopZ forms condensates at the poles of bacterium Caulobacter crescentus, which turn orchestrate cell-cycle regulating signaling cascades. Here we show that properties are determined by balance...
In the past almost 15 years, we witnessed birth of a new scientific field focused on existence, formation, biological functions, and disease associations membraneless bodies in cells, now referred to as biomolecular condensates. Pioneering studies from several laboratories [reviewed in1, 2, 3] supported model wherein condensates associated with diverse processes form through process phase separation. These other findings that followed have revolutionized our understanding how biomolecules...
Copy Number Variations (CNVs) and Single Nucleotide Polymorphisms (SNPs) have been the major focus of most large-scale comparative genomics studies to date. Here, we discuss a third, largely ignored, type genetic variation, namely changes in tandem repeat number. Historically, repeats designated as non functional "junk" DNA, mostly result their highly unstable nature. With exception involved human neurodegenerative diseases, variation was often believed be neutral with no phenotypic...
Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role these consequences more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains highly enriched eukaryotic transcription factors where they act functional modulators. Incremental changes number yeast transcriptional regulator Ssn6 (Cyc8) systematic,...
The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: RNA toxicity dipeptide protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine–arginine proline–arginine, induced motor axonopathy. Similarly, expanded sense antisense also axonopathy formed mainly...
RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which mutated aggregated in both ALS FTLD. We generated Drosophila model FUS toxicity identified previously unrecognized synergistic effect between N-terminal prion-like domain C-terminal arginine-rich to...
A hexanucleotide repeat expansion in the C9orf72 gene is most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell-derived motor neurons that impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating from healthy individuals with proline-arginine glycine-arginine...
TDP-43 is the major component of pathological inclusions in most ALS patients and up to 50% with frontotemporal dementia (FTD). Heterozygous missense mutations TARDBP, gene encoding TDP-43, are one common causes familial ALS. In this study, we investigate protein behavior induced pluripotent stem cell (iPSC)-derived motor neurons from three different TARDBP mutations, healthy controls an isogenic control. TARDPB induce several changes spinal neurons, including cytoplasmic mislocalization...
Abstract Repeat expansions in the C9orf72 gene cause amyotrophic lateral sclerosis and frontotemporal dementia characterized by dipeptide-repeat protein (DPR) inclusions. The toxicity associated with two of these DPRs, poly-GR poly-PR, has been nucleocytoplasmic transport. To investigate causal role or poly-PR on active transport, we measured nuclear import export expressing Hela cells, neuronal-like SH-SY5Y cells iPSC-derived motor neurons. Our data strongly indicate that do not directly impede
Abstract Increasingly, repeat expansions are being identified as part of the complex genetic architecture amyotrophic lateral sclerosis. To date, several have been genetically associated with disease: intronic in C9orf72, polyglutamine ATXN2 and polyalanine NIPA1. Together previously published data, identification an sclerosis patient a family history spinocerebellar ataxia type 1, caused by ATXN1, suggested similar disease association for expansion ATXN1. We, therefore, performed...
Abstract Phase separation is emerging as a universal principle for how cells use dynamic subcompartmentalization to organize biochemical reactions in time and space 1,2 . Yet, whether the emergent physical properties of these biomolecular condensates are important their biological function remains unclear. The intrinsically disordered protein PopZ forms membraneless at poles bacterium Caulobacter crescentus selectively sequesters kinase-signaling cascades regulate asymmetric cell division...
Mutations in the ataxin-2 gene (ATXN2) cause neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic strategy using antisense oligonucleotides targeting ATXN2 has entered clinical trial humans. Additional ways to decrease levels could lead cheaper or less invasive therapies elucidate how is normally regulated. Here, we perform a genome-wide fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen human cells identify...
Positively charged repeat peptides are emerging as key players in neurodegenerative diseases. These can perturb diverse cellular pathways but a unifying framework for how such promiscuous toxicity arises has remained elusive. We used mass-spectrometry-based proteomics to define the protein targets of these neurotoxic and found that they all share similar sequence features drive their aberrant condensation with positively peptides. trained machine learning algorithm detect unexpectedly...