A5008078031- Hearing, Cochlea, Tinnitus, Genetics
- Retinal Development and Disorders
- Hereditary Neurological Disorders
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA modifications and cancer
- RNA regulation and disease
- Cellular Mechanics and Interactions
- Genetic Neurodegenerative Diseases
- Erythrocyte Function and Pathophysiology
- Mitochondrial Function and Pathology
- Biochemical and Molecular Research
- Cellular transport and secretion
- Genomics and Rare Diseases
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Neurobiology and Insect Physiology Research
- Signaling Pathways in Disease
- Genomics and Chromatin Dynamics
- Muscle Physiology and Disorders
- Neuroscience, Education and Cognitive Function
- Histone Deacetylase Inhibitors Research
- Animal Vocal Communication and Behavior
- S100 Proteins and Annexins
- Neurological diseases and metabolism
Jackson Laboratory
2015-2024
Max Planck Institute for Heart and Lung Research
2023
Tufts University
2023
National Institute on Deafness and Other Communication Disorders
2023
Johns Hopkins University
2011
Heterozygous mutations in six transfer RNA (tRNA) synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT mutant tRNA synthetases inhibit protein synthesis by an unknown mechanism. We found that glycyl-tRNA bound tRNAGly but failed to release it, resulting sequestration. This sequestration potentially depleted the cellular pool, leading insufficient glycyl-tRNAGly supply ribosome. Accordingly, we ribosome stalling at glycine codons and activation of integrated stress...
Defeating peripheral neuropathy The mechanisms underlying neuropathies are not well understood. Spaulding et al . studied mouse models of the inherited Charcot-Marie-Tooth (CMT) disease, which is caused by mutations in transfer RNA (tRNA) synthetases. Changes gene expression and rate protein synthesis neurons spinal cord triggered cell stress response activated sensor GCN2. When GCN2 was genetically deleted or inhibited with drugs, blocked, much milder. Zuko found that mutant glycyl-tRNA...
Bardet-Biedl syndrome (BBS) is a pleiotropic, heterogeneous human disease whose etiology lies primarily in dysfunctional basal bodies and/or cilia. Both BBS patients and several mouse models exhibit impaired olfactory function. To explore the nature of defects BBS, genetic ablation Bbs8 gene that incorporates fluorescent reporter protein was created. The endogenous BBS8 are particularly abundant sensory neurons (OSNs), specific antibodies reveal staining dendritic knob shell-like structure...
Sensory perception in the inner ear relies on hair bundle, highly polarized brush of movement detectors that crowns cells. We previously showed that, mouse cochlea, edge forming bundle is defined by 'bare zone', a microvilli-free sub-region apical membrane specified Insc-LGN-Gαi protein complex. now report LGN and Gαi also occupy very tip stereocilia directly abut bare zone. demonstrate are both essential for promoting elongation differential identity across rows. Interestingly, we reveal...
Abstract Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated neurological disorders, most notably inherited peripheral neuropathies. ARSs enzymes that charge tRNA molecules with cognate amino acids. asparaginyl-tRNA (NARS1) cause a phenotype combining developmental delay, ataxia and demyelinating neuropathy. NARS1 has not yet been linked to axonal Charcot–Marie–Tooth disease. Exome sequencing of patients neuropathies revealed three previously unreported...
Spontaneously arising mouse mutations have served as the foundation for understanding gene function more than 100 years. We used exome sequencing in an effort to identify causative 172 distinct, spontaneously models of Mendelian disorders, including a broad range clinically relevant phenotypes. To analyze resulting data, we developed analytics pipeline that is optimized data and variation database allows reproducible, user-defined mining well nomination mutation candidates through...
Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk bidirectional regulation of their dynamics in health disease. However, mitochondria–lysosome misregulation have not been investigated peripheral sensory neurons. Charcot–Marie–Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting neurons caused by mutations GTPase Rab7. Using live super-resolution confocal time-lapse microscopy, we showed that dynamically form soma axons Interestingly,...
The promise of personalized medicine is that each patient's treatment can be optimally tailored to their disease. In turn, disease, as well response the treatment, determined by genetic makeup and "environment," which relates general health, medical history, personal habits, surroundings. Developing such optimized strategies an admirable goal success stories include examples switching chemotherapy agents based on a tumor genotype. However, it remains challenge apply precision diseases for...
Many of the models neurodevelopmental processes such as cell migration, axon outgrowth, and dendrite arborization involve adhesion chemoattraction critical physical or mechanical aspects mechanism. However, prevention attraction is under-appreciated a necessary, active process that balances these forces, insuring correct cells are present adhering in place at time. The phenomenon not often viewed passive alternative to adhesion, some cases this may be true. it becoming increasingly clear...
Abstract Animal models of neurodegenerative diseases such as inherited peripheral neuropathies sometimes accurately recreate the pathophysiology human disease, and genetic perturbations found in patients. Ideally, achieve both, but this is not always possible; nonetheless, are informative. Here we describe two animal neuropathy: mice with a mutation tyrosyl tRNA‐synthetase, Yars E196K , modeling dominant intermediate Charcot‐Marie‐Tooth disease type C (diCMTC), serine palmitoyltransferase...
Abstract Background Inhibition of HDAC6 has been proposed as a broadly applicable therapeutic strategy for Charcot–Marie–Tooth disease (CMT). increases the acetylation proteins important in axonal trafficking, such α‐tubulin and Miro, shown to be efficacious several preclinical studies using mouse models CMT. Aims Here, we sought expand on previous by testing effect genetic deletion Hdac6 mice carrying humanized knockin allele Gars1 , model CMT‐type 2D. Methods ΔETAQ were bred an knockout...
Different types of neurons in the retina are organized vertically into layers and horizontally a mosaic pattern that helps ensure proper neural network formation information processing throughout visual field. The vertebrate Dscams (DSCAM DSCAML1) cell adhesion molecules support development this organization by promoting self-avoidance at level types, normal developmental death, directing vertical neurite stratification. To understand molecular interactions required for these activities, we...
Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and hearing. The extent nature their actual contributions remains unclear, however, as previous studies did not investigate all GNAI included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, GNAO proteins, but may also induce unrelated defects. Here, we directly systematically determine role(s) each individual protein in mouse...
Mutations in the gene encoding immunoglobulin-superfamily member cell adhesion molecule contactin1 (CNTN1) cause lethal congenital myopathy human patients and neurodevelopmental phenotypes knockout mice. Whether mutant mice provide an accurate model of disease is unclear; resolving this will require additional functional tests neuromuscular system examination Cntn1 mutations on different genetic backgrounds that may influence phenotype. Toward these ends, we have analyzed a new, spontaneous...
Abstract Background Charcot–Marie–Tooth disease type 1X is caused by mutations in GJB1 , which the second most common gene associated with inherited peripheral neuropathy. The encodes connexin 32 (CX32), a gap junction protein expressed myelinating glial cells. X‐linked, and cause loss of function. Aims A large number disease‐associated variants have been identified, many result mistrafficking mislocalization protein. An existing knockout mouse lacking Gjb1 expression provides valid animal...
The final step in proline biosynthesis is catalyzed by three pyrroline-5-carboxylate reductases, PYCR1, PYCR2, and PYCR3, which convert (P5C) to proline. Mutations human PYCR1 ALDH18A1 (P5C Synthetase) cause Cutis Laxa (CL), whereas mutations PYCR2 hypomyelinating leukodystrophy 10 (HLD10). Here, we investigated the genetics of Pycr1 Pycr2 mice. A null allele did not show integument or CL-related phenotypes. We also studied a novel chemically-induced mutation Pycr2. Mice with recessive...
Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and hearing. The extent nature their actual contributions remains unclear, however, as previous studies did not investigate all GNAI included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, GNAO proteins, but may also induce unrelated defects. Here, we directly systematically determine role(s) each individual protein in mouse...
Abstract NADK2 encodes the mitochondrial form of nicotinamide adenine dinucleotide (NAD) kinase, which phosphorylates NAD. Rare recessive mutations in human are associated with a syndromic neurological disease that includes metabolic changes, such as hyperlysinemia and 2,4 dienoyl CoA reductase (DECR) deficiency. However, full pathophysiology resulting from deficiency is not known. Here, we describe two chemically induced mouse Nadk2—S326L S330P—which cause severe neuromuscular shorten...
Abstract The Retinoid-related orphan receptor beta (RORβ) gene encodes a developmental transcription factor and has 2 predominant isoforms created through alternative first exon usage; one specific to the retina another present more broadly in central nervous system, particularly regions involved sensory processing. RORβ belongs nuclear family plays important roles cell fate specification cortical layer formation. In mice, loss of causes disorganized layers, postnatal degeneration,...
Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and hearing. The extent nature their actual contributions remains unclear, however, as previous studies did not investigate all GNAI included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3 GNAO proteins, but may also induce unrelated defects. Here we directly systematically determined role(s) each individual protein in mouse...
It has become increasingly appreciated that autoimmune responses against neuronal components play an important role in type 1 diabetes (T1D) pathogenesis. In fact, a large proportion of islet-infiltrating B lymphocytes the NOD mouse model T1D produce Abs directed III intermediate filament protein peripherin. NOD-PerIg mice are previously developed BCR-transgenic which virtually all express H and L chain Ig molecules from intra-islet-derived anti-peripherin-reactive hybridoma H280. have...
Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating peripheral neuropathy caused by the duplication of myelin protein 22 (PMP22), leading to muscle weakness and loss sensation in hands feet. A recent case-only genome-wide association study CMT1A patients conducted Inherited Neuropathy Consortium identified strong between strength foot dorsiflexion variants signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be genetic modifier disease. To validate...