A5003246271- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Prion Diseases and Protein Misfolding
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- RNA modifications and cancer
- Endoplasmic Reticulum Stress and Disease
- Neurological diseases and metabolism
- Alzheimer's disease research and treatments
- Chromosomal and Genetic Variations
- CRISPR and Genetic Engineering
- Fungal and yeast genetics research
- ATP Synthase and ATPases Research
University of Pennsylvania
2021-2024
University of Pittsburgh
2019-2022
Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, role RBP in specificity and function protein-RNA complexes remains unclear. We created a series TDP-43 C-terminal domain (CTD) variants that exhibited gradient low to high propensity, as observed vitro by nuclear mobility foci formation. Notably, capacity for was required efficient assembly on subsets regions, which contain unusually long clusters motifs...
Abstract A G4C2 hexanucleotide repeat expansion in the C9orf72 gene is most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed regions neurodegeneration. The accumulation repetitive RNAs dipeptide protein (DPR) are two proposed mechanisms toxicity C9-ALS/FTLD linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport regulated by phenylalanine-glycine nucleoporins (FG nups) that comprise nuclear pore complex (NPC) permeability...
Abstract Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense variants TARDBP , the gene encoding TDP-43, can cause ALS cluster C-terminal prion-like domain (PrLD), where they modulate liquid condensation aggregation properties of protein. also found rimmed vacuole myopathies, including sporadic inclusion body myositis, but myopathy-causing TDP-43 have not been reported. Using...
Cytoplasmic aggregation and concomitant dysfunction of the prion-like, RNA-binding protein TDP-43 underpin several fatal neurodegenerative diseases, including amyotrophic lateral sclerosis. To elucidate endogenous defenses, we systematically scoured entire human Hsp70 network for buffers toxicity. We identify 30 J-domain proteins (2 DNAJAs, 10 DNAJBs, 18 DNAJCs), 6 Hsp70s, 5 nucleotide-exchange factors that mitigate Specific chaperones reduce aggregate burden detoxify diverse synthetic or...
RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) prevent fibrillization by promoting liquid phases, distinct and, remarkably, reverse condensation fibrillization. These activities require interactions multiple domains of are...
The presence of large protein inclusions is a hallmark neurodegeneration, and yet the precise molecular factors that contribute to their formation remain poorly understood. Screens using aggregation-prone proteins have commonly relied on downstream toxicity as readout rather than direct aggregates. Here, we combined genome-wide CRISPR knockout screen with Pulse Shape Analysis, FACS-based method for inclusion detection, identify modifiers TDP-43 aggregation in human cells. Our revealed both...
Abstract Aberrant aggregation of the prion-like, RNA-binding protein TDP-43 underlies several debilitating neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). Here, we define how short, specific RNAs antagonize aggregation. Short, engage and stabilize RNA-recognition motifs, which allosterically destabilizes a conserved helical region in prion-like domain, thereby promoting aggregation-resistant conformers. By mining sequence space, uncover short with enhanced...
Abstract Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) share clinical, neuropathological, genetic features. This includes common disease-causing mutations such as the expanded G4C2 repeat in C9orf72 gene (C9-ALS/FTLD) cytoplasmic insoluble protein depositions of TDP-43 degenerating regions brain spinal cord. Proposed mechanisms toxicity C9-ALS/FTLD are production expansion transcripts their dipeptide proteins (DPRs) products which hypothesized to drive...
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both fatal neurodegenerative disorders characterized by neuronal loss. ALS is primarily motor impairments stemming from degeneration of neurons, whereas the main symptoms FTD include changes in personality, behavior, language cortical neurons frontal temporal lobes. exist on a clinical continuum, where some patients present with features diseases. A molecular hallmark shared almost all approximately half pathological...