A5037193962- Heat shock proteins research
- Muscle Physiology and Disorders
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Neurogenetic and Muscular Disorders Research
- RNA modifications and cancer
- Cardiomyopathy and Myosin Studies
- Ubiquitin and proteasome pathways
- Genomics and Chromatin Dynamics
- Amyotrophic Lateral Sclerosis Research
- RNA regulation and disease
- Muscle metabolism and nutrition
- Exercise and Physiological Responses
- Endoplasmic Reticulum Stress and Disease
- DNA Repair Mechanisms
- Neurological disorders and treatments
- Cancer-related gene regulation
- Cell death mechanisms and regulation
- Cancer-related Molecular Pathways
- Neurology and Historical Studies
- Cardiovascular Effects of Exercise
- Neurological diseases and metabolism
- Enzyme Structure and Function
- Cancer-related molecular mechanisms research
- Glycogen Storage Diseases and Myoclonus
Washington University in St. Louis
2013-2024
Hope Center for Neurological Disorders
2017-2019
Harbor–UCLA Medical Center
2019
UCLA Medical Center
2019
Universidad de Cantabria
2006-2014
Centro de Investigación Biomédica en Red
2012
Biomedical Research Networking Center on Neurodegenerative Diseases
2008-2012
Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G 2 /M cell cycle arrest induced by DNA damage, but little is known about this signaling pathway 1 /S transition.Upregulation cyclin-dependent inhibitor p21 Cip1 thought to make a major contribution ␥ radiation.We show here that inhibition MAPK impairs accumulation and, as result, ability cells response found induces mRNA stabilization, without affecting its transcription or stability protein.In...
TDP-43 aggregation in the cytoplasm or nucleus is a key feature of pathology amyotrophic lateral sclerosis and frontotemporal dementia observed numerous other neurodegenerative diseases, including Alzheimer's disease. Despite this fact, inciting events leading to remain unclear. We that endogenous undergoes reversible after heat shock behavior mediated by C-terminal prion domain. Substitution domain from TIA-1 an authentic yeast RNQ1 into can completely recapitulate shock-induced...
BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via isoleucine-proline-valine (IPV) motifs and Hsp70 BAG domain. Mutations in either the IPV or domain cause dominant form myopathy, characterized by protein aggregation both skeletal cardiac muscle tissues. Surprisingly, for disease mutants, impaired chaperone binding not sufficient to explain phenotypes. Recombinant mutants are correctly folded, show unaffected but stimulating...
Limb-girdle muscular dystrophy type 1D (LGMD1D) is caused by dominantly inherited missense mutations in DNAJB6, an Hsp40 co-chaperone. LGMD1D muscle has rimmed vacuoles and inclusion bodies containing Z-disc proteins TDP-43. DNAJB6 expressed as two isoforms; DNAJB6a DNAJB6b. Both isoforms contain mutant residues are human muscle. To identify which isoform confers disease pathogenesis generate a mouse model of LGMD1D, we evaluated expression localization skeletal well generating specific...
Genomic instability at loci with tandem arrays of simple repeats is the cause for many neurological, neurodegenerative and neuromuscular diseases. When located in coding regions, disease-associated expansions trinucleotide are translated into homopolymeric amino acid stretches glutamine or alanine. Polyalanine poly(A)-binding protein nuclear 1 (PABPN1) gene causes oculopharyngeal muscular dystrophy (OPMD). To gain novel insight molecular pathophysiology OPMD, we studied interaction cellular...
Dominant mutations in the HSP70 cochaperone DNAJB6 cause a late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease reside within G/F domain of DNAJB6, but molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, mouse models LGMDD1, we found that toxicity associated with disease-associated required its interaction abrogating this genetically or...
Cajal bodies (CBs) are nuclear organelles involved in the maturation of spliceosomal snRNPs. They concentrate coilin, snRNPs and survival motor neuron protein (SMN). Dysfunction CB assembly is an essential component spinal muscular atrophy (SMA). Here we demonstrate that SMN a SUMO1 target has SUMO-like interacting motif (SIM-like) Tudor domain. The expression SIM-like mutant constructs abolishes interaction with SmD1, severely decreases SMN-coilin prevents assembly. Accordingly,...
To understand DNAJB6's function in skeletal muscle and identify therapeutic targets for limb-girdle muscular dystrophy 1D (LGMD1D).DNAJB6 knockout (KO) myoblasts were generated with Crispr/cas9 technology, differentially accumulated proteins identified using stable isotope labeling, followed by quantitative mass spectrometry. Cultured KO myotubes mouse from DNAJB6b-WT or DNAJB6b-F93L mice analyzed histochemistry, immunohistochemistry, immunoblot. Mouse functional strength measures included...
Abstract Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays vital role cellular proteostasis. Recessive loss-of-function cause myopathy with early respiratory failure spinal rigidity, presenting infancy adulthood. This study investigated broader clinical genetic spectrum of myopathy. In this study, we performed whole-exome sequencing on seven patients...
Dominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations muscle. Mutations reside both isoforms, yet evidence suggests that DNAJB6b is primarily responsible for disease pathogenesis. Knockdown treatment strategies involving carry risk, as DNAJB6 knockout embryonic lethal. We therefore developed an isoform-specific knockdown...