Principal Scientist at GSK • Still learning Previously: JHU, UPenn, UNC-CH 🧬🦠🔬🧠🐈🌱
Rapid removal of nuclear aggregates via proteasome- and VCP-dependent disaggregation www.biorxiv.org/content/10.6...
Rapid removal of nuclear aggregates via proteasome- and VCP-dependent disaggregationCells use multiple protein quality control (PQC) mechanisms to counteract the toxic effects of protein aggregation caused by cellular stress, ageing or disease. While it is known that PQC mechanisms d...www.biorxiv.orgTherapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice rdcu.be/fr71m
Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis miceNature Aging - Gao et al. identify a toxicity-driving region within TDP-43 and show that a brain-penetrant small molecule targeting this region improves mitochondrial function, reduces...rdcu.beADAR2-Mediated RNA Editing Promotes TDP-43 Nuclear Export and Alters RNA Binding www.biorxiv.org/content/10.6...
ADAR2-Mediated RNA Editing Promotes TDP-43 Nuclear Export and Alters RNA BindingBACKGROUND TAR DNA binding protein - 43 (TDP-43) nuclear loss is a pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related neurodegenerative disorders....www.biorxiv.orgAn emergent disease-associated motor neuron state precedes cell death in ALS www.cell.com/cell/fulltex...
An emergent disease-associated motor neuron state precedes cell death in ALSLongitudinal multi-omics in SOD1-ALS mice identifies a disease-associated motor neuron
(DM) state transition driven by transcription factor networks. Features of this state
are conserved in human ALS ...www.cell.commRNA-Scaffolded Cytoplasmic Compartments www.annualreviews.org/content/jour...
mRNA-Scaffolded Cytoplasmic CompartmentsThe cytoplasm of vertebrate cells is compartmentalized into the cytosol and several messenger RNA (mRNA)-scaffolded condensates, present at steady-state conditions and in the absence of stress. They i...www.annualreviews.orgTau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior www.biorxiv.org/content/10.6...
Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and BehaviorPathological tau aggregates drive neuronal dysfunction in Alzheimer’s disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the...www.biorxiv.orgTDP-43 self-assembly is regulated by its disordered NLS-region www.biorxiv.org/content/10.6...
TDP-43 self-assembly is regulated by its disordered NLS-regionCytosolic inclusions of the RNA-binding protein TDP-43 are a pathological hallmark of several neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Cellular or...www.biorxiv.orgCircular RNA aptamers act as superb sub-stoichiometric chaperones to prevent cytosolic TDP-43 condensation www.biorxiv.org/content/10.6...
Circular RNA aptamers act as superb sub-stoichiometric chaperones to prevent cytosolic TDP-43 condensationPathological protein misfolding and aggregation underlie many devastating human diseases, yet strategies to selectively neutralize aggregation-prone protein states without perturbing their normal func...www.biorxiv.orgHigh-throughput screening approach identifies substrate-selective Hsp104 variants that counter amyloid seeding with diminished off-target effects www.cell.com/molecular-ce...
High-throughput screening approach identifies substrate-selective Hsp104 variants that counter amyloid seeding with diminished off-target effectsRyan et al. have developed a high-throughput approach for identifying variants of
the amyloid disaggregase Hsp104. Their approach facilitates analysis of large Hsp104
variant libraries in parallel and...www.cell.comRNA imbalance as a hallmark of cellular ageing rdcu.be/fikJl
RNA imbalance as a hallmark of cellular ageingNature Cell Biology - This Perspective highlights the failures of an ageing cell in properly maintaining mRNA health at the various steps of the mRNA life cycle that result in vulnerability to...rdcu.beRational Design of a Multivalent RNA Combining Structural Motifs Tailored to Multiple Domains of Fused in Sarcoma for Potent Inhibition of Aggregation chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1...
Rational Design of a Multivalent RNA Combining Structural Motifs Tailored to Multiple Domains of Fused in Sarcoma for Potent Inhibition of AggregationFused in sarcoma (FUS) is an RNA-binding protein whose pathological aggregation via aberrant phase separation contributes to amyotrophic lateral sclerosis (ALS). Although RNA can modulate the phase b...chemistry-europe.onlinelibrary.wiley.comPredictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification www.biorxiv.org/content/10.6...
www.biorxiv.orgRoles of RNA-Binding Nuclear Proteins in Alzheimer’s Disease Pathophysiology pubs.acs.org/doi/full/10....
Roles of RNA-Binding Nuclear Proteins in Alzheimer’s Disease PathophysiologyAlzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive decline. Pathologically, AD is characterized by the accumulation of amyloid β (Aβ) monomers that may generate oligome...pubs.acs.orgRanGAP1 accumulates in stress-induced cytoplasmic compartments that are distinct from stress granules and P-bodies doi.org/10.17912/mic...
RanGAP1 accumulates in stress-induced cytoplasmic compartments that are distinct from stress granules and P-bodies | microPublicationdoi.orgA quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms dx.plos.org/10.1371/jour...
A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanismsTDP-43 pathology is a hallmark of several neurodegenerative disorders, but the connection between TDP-43 aggregation and dysfunction remains poorly understood. This study develops a quantitative cell-...dx.plos.orgMembrane-associated Rhes-Slc4a7 complex orchestrates tunneling nanotube formation and mutant Huntingtin spread www.science.org/doi/10.1126/...
Membrane-associated Rhes-Slc4a7 complex orchestrates tunneling nanotube formation and mutant Huntingtin spreadRhes-Slc4a7 membrane signaling drives TNT formation and mHTT spread, revealing a therapeutic target in Huntington disease.www.science.orgSubtyping based on hippocampal cryptic exon burden reveals proteome-wide changes associated with TDP-43 and Alzheimer’s disease pathology www.sciencedirect.com/science/arti...
Subtyping based on hippocampal cryptic exon burden reveals proteome-wide changes associated with TDP-43 and Alzheimer’s disease pathologyTDP-43 pathology defines limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and frequently co-occurs with Alzheimer’s disease neuropatholo…www.sciencedirect.comC9ORF72-derived polyGR polypeptides disrupt passive nucleocytoplasmic transport by tuning protein affinity for the nuclear pore barrier www.biorxiv.org/content/10.6...
www.biorxiv.orgCofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis academic.oup.com/brain/articl...
Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosisJones Jagaraj et al. show that cofilin is hyperphosphorylated in postmortem spinal cord tissue from patients with sporadic ALS, disrupting actin dynamics aacademic.oup.com