A5084836766- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- Heat shock proteins research
- Prion Diseases and Protein Misfolding
- Endoplasmic Reticulum Stress and Disease
- Genetics, Aging, and Longevity in Model Organisms
- Neurogenetic and Muscular Disorders Research
- Protein Structure and Dynamics
- RNA modifications and cancer
- Enzyme Structure and Function
- Genetic Neurodegenerative Diseases
- RNA and protein synthesis mechanisms
- Alzheimer's disease research and treatments
- Cellular transport and secretion
- Mitochondrial Function and Pathology
- Neurological diseases and metabolism
- Nuclear Structure and Function
- RNA regulation and disease
- Lipid Membrane Structure and Behavior
- Fungal and yeast genetics research
- Parkinson's Disease Mechanisms and Treatments
- Bacterial Genetics and Biotechnology
- Proteins in Food Systems
- Ubiquitin and proteasome pathways
- HIV Research and Treatment
University of Pennsylvania
2016-2025
California University of Pennsylvania
2021-2024
Philadelphia University
2008-2024
University of South Dakota
2022
Institute of Molecular Biology and Biophysics
2021
Whitehead Institute for Biomedical Research
2002-2016
University of California, Berkeley
2016
Clifford Chance
2013
Howard Hughes Medical Institute
2007
Ludwig Cancer Research
2002
Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, frontotemporal lobar degeneration with ubiquitin-positive (FTLD-U). Importantly, mutations linked to sporadic non-SOD1 familial ALS. However, is not the only protein in disease-associated inclusions, whether misfolds or merely sequestered by other aggregated components unclear. Here, we report that,...
alpha-Synuclein (alpha-syn), a protein of unknown function, is the most abundant in Lewy bodies, histological hallmark Parkinson's disease (PD). In yeast alpha-syn inhibits endoplasmic reticulum (ER)-to-Golgi (ER-->Golgi) vesicle trafficking, which rescued by overexpression Rab GTPase that regulates ER-->Golgi trafficking. The homologous Rab1 rescues toxicity dopaminergic neuronal models PD. Here we investigate this conserved feature pathobiology. cell-free system with purified transport...
The protein-remodeling factor Hsp104 governs inheritance of [PSI+], a yeast prion formed by self-perpetuating amyloid conformers the translation termination Sup35. Perplexingly, either excess or insufficient eliminates [PSI+]. In vitro, at low concentrations, catalyzed formation oligomeric intermediates that proved critical for nucleation Sup 35 fibrillization de novo and displayed conformation common among amyloidogenic polypeptides. At higher oligomerization contingent were abolished. also...
TDP-43 and FUS are RNA-binding proteins that form cytoplasmic inclusions in some forms of amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). Moreover, mutations linked to ALS FTLD. However, it is unknown whether aggregate cause toxicity by similar mechanisms. Here, we exploit a yeast model purified elucidate mechanisms aggregation toxicity. Like TDP-43, must the cytoplasm bind RNA confer yeast. These aggregates partition stress granule compartments just as they do...
Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS TDP-43, raising the possibility additional might contribute to ALS pathogenesis. We performed systematic survey these find candidates similar followed by bioinformatics predict domains subset...
Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is depletion RNA-binding protein TDP-43 from nucleus neurons in brain spinal cord 1 . major function as a repressor cryptic exon inclusion during RNA splicing 2–4 Single nucleotide polymorphisms UNC13A are among strongest hits associated with FTD ALS human genome-wide association studies 5,6 , but how those variants increase risk for disease...
Bacteria, fungi, protozoa, chromista and plants all harbor homologues of Hsp104, a AAA+ ATPase that collaborates with Hsp70 Hsp40 to promote protein disaggregation reactivation. Curiously, however, metazoa do not possess an Hsp104 homologue. Thus, whether animal cells renature large aggregates has long remained unclear. Here, it is established mammalian cytosol prepared from different sources possesses potent, ATP-dependent disaggregase reactivation activity, which can be accelerated...
Prions are proteins that access self-templating amyloid forms, which confer phenotypic changes can spread from individual to within or between species. These infectious phenotypes be beneficial, as with yeast prions, deleterious, mammalian prions transmit spongiform encephalopathies. However, the ability form is not unique prion proteins. Diverse polypeptides tend populate intrinsically unfolded states also conformers associated devastating neurodegenerative disorders. Moreover, two...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These three share several features, including the presence of bioinformatics-predicted prion domain, aggregation–prone nature vitro vivo toxic effects when expressed multiple model systems. Given these commonalities, we hypothesized that protein, EWSR1 (Ewing sarcoma breakpoint region 1), might also...
Untangling aggregates one step at a time Conserved AAA+ protein complexes exploit adenosine triphosphate hydrolysis to unfold and disaggregate their substrates in response cell stress, but exactly how they do this has been unclear. Gates et al. determined high-resolution cryo-electron microscopy structures of the Hsp104 disaggregase bound an unfolded polypeptide substrate its channel. The reveal interactions two different translocation states. undergoes conformational changes that drive...
Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how cause neurodegeneration. Using transgenic mice expressing a common FALS-associated mutation (FUS-R521C mice), we found that mutant proteins formed stable complex with WT and interfered normal interactions between histone deacetylase 1 (HDAC1). Consequently, FUS-R521C exhibited evidence DNA damage as well profound dendritic synaptic...