A5063084545- Muscle Physiology and Disorders
- Neurogenetic and Muscular Disorders Research
- Amyotrophic Lateral Sclerosis Research
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Cardiomyopathy and Myosin Studies
- Hereditary Neurological Disorders
- Neurological diseases and metabolism
- Ubiquitin and proteasome pathways
- Adipose Tissue and Metabolism
- Viral Infections and Immunology Research
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA regulation and disease
- Biotin and Related Studies
- Statistical Methods and Inference
- Cellular transport and secretion
- Viral Infectious Diseases and Gene Expression in Insects
- Genetics and Neurodevelopmental Disorders
- Histone Deacetylase Inhibitors Research
- Respiratory viral infections research
- Cancer-related gene regulation
- Silk-based biomaterials and applications
- Genetics and Physical Performance
Jackson Laboratory
2014-2024
University of Maine
2016-2024
Tufts University
2022
The Graduate Center, CUNY
2021-2022
Eli Lilly (United States)
1995-2021
Johns Hopkins Medicine
2021
Johns Hopkins University
2021
New York Genome Center
2018
Oak Ridge National Laboratory
2013
National Technical Information Service
2013
Variants of UNC13A, a critical gene for synapse function, increase the risk amyotrophic lateral sclerosis and frontotemporal dementia
Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated introduction γ-sarcoglycan-null allele onto DBA/2J confers a more severe dystrophy than original strain, demonstrating presence modifier loci background. To characterize dystrophin deficiency on background, we created and phenotyped...
The "housekeeping" sodium/hydrogen exchanger, NHE1, mediates the electroneutral 1:1 exchange of Na+ and H+ across plasma membrane. NHE1 is ubiquitous studied extensively for regulation pH i, cell volume, response to growth factors. We describe a spontaneous mouse mutant, s low-w ave e pilepsy, (swe), with neurological syndrome including ataxia unique epilepsy phenotype consisting 3/sec absence tonic-clonic seizures. swe was fine-mapped on Chromosome 4 identified as null allele Nhe1. Mutants...
Limb girdle muscular dystrophy type 2B and Miyoshi myopathy are clinically distinct forms of that arise from defects in the dysferlin gene. Here, we report two novel lines dysferlin-deficient mice obtained by (a) gene targeting (b) identification an inbred strain, A/J, bearing a retrotransposon insertion The mutations these were located at 3′ 5′ ends Both lacked developed progressive with histopathological ultrastructural features closely resemble human disease. Vital staining Evans blue dye...
Neural activity actively regulates muscle gene expression. This regulation is crucial for specifying functionality and synaptic protein How neural relayed into nuclei connected to the transcriptional machinery, however, not known. Here we identify histone deacetylase HDAC4 as critical linker connecting transcription. We found that normally concentrated at neuromuscular junction (NMJ), where nerve innervates muscle. Remarkably, reduced input by surgical denervation or diseases dissociates...
Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by weakness and hypotonia in early infancy. A number genes harboring causative mutations have been identified, but several cases congenital remain molecularly unresolved. We examined 15 individuals with early-onset wasting, mental retardation, peculiar enlarged mitochondria that are prevalent toward the periphery fibers sparse center on biopsy, we identified homozygous or compound...
Embryogenesis is a highly regulated process in which the precise spatial and temporal release of soluble cues directs differentiation multipotent stem cells into discrete populations specialized adult cell types. In spinal cord, neural progenitor are directed to differentiate neurons through action mediators released from nearby organizing centers, such as floor plate paraxial mesoderm. These signals combine create spatiotemporal diffusional landscapes that precisely regulate development...
A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to mice. Whether results from RQC whether contributes human disease have remained unknown. Here we show that three independently-generated mouse models with mutations different component the...
TDP-43 (TAR DNA-binding protein 43) aggregation and redistribution are recognised as a hallmark of amyotrophic lateral sclerosis frontotemporal dementia. As inclusions have recently been described in the muscle inclusion body myositis patients, this highlights need to understand role beyond central nervous system. Using RNA-seq, we directly compare TDP-43-mediated RNA processing (C2C12) neuronal (NSC34) mouse cells. displays cell-type-characteristic behaviour targeting unique transcripts...
Dystrophin plays an important role in skeletal muscle by linking the cytoskeleton and extracellular matrix. The amino terminus of dystrophin binds to actin possibly other components subsarcolemmal cytoskeleton, while carboxy associates with a group integral peripheral membrane proteins glycoproteins that are collectively known as dystrophin-associated protein (DAP) complex. We have generated transgenic/mdx mice expressing "full-length" constructs, but consecutive deletions within...
The effective treatment or cure of motoneuron disease will require understanding the processes that precede irreversible cell loss. To study these early stages, and to evaluate potential treatments in relevant animal models, requires a sensitive functional assay. this end, we sought determine whether gait pattern SOD1 transgenic mice changed prior overt symptoms. Using simplified video-based approach compared treadmill C57BL/6J B6.SOD1 at 8 10 weeks age. had significantly longer stride...
ALS2/alsin is a member of guanine nucleotide exchange factors for the small GTPase Rab5 (Rab5GEFs), which act as modulators in endocytic pathway. Loss-of-function mutations human ALS2 account number juvenile recessive motor neuron diseases (MNDs). However, normal physiological role vivo and molecular mechanisms underlying dysfunction are still unknown. To address these issues, we have generated mice homozygous disruption Als2 gene. The Als2-null observed through 21 months age demonstrated no...
The mitochondrial metalloprotease AFG3L2 assembles with the homologous protein paraplegin to form a supracomplex in charge of essential quality control within mitochondria. Mutations cause specific axonal degeneration upper motoneuron and, therefore, hereditary spastic paraplegia. Here we present two Afg3l2 murine models: newly developed null and spontaneous mutant that found carrier missense mutation. Contrasting mild late onset paraplegin-deficient mouse, models display marked impairment...
Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 homo-oligomeric complexes in the inner membrane, named m -AAA proteases. These ensure protein quality control jointly with a chaperone-like activity on respiratory chain complexes. Despite coassembling same complex, mutations of either paraplegin or cause two different neurodegenerative disorders. Indeed, responsible for recessive hereditary spastic paraplegia, whereas...
Mistress of Meiosis is essential for proper distribution maternal chromosomes to eggs during oogenesis. Su et al. (p. 1496 ) identified a gene, meiosis arrest female 1 ( Marf1 ), which indispensable and other oogenic processes. In mice, mutations resulted in meiotic an increase nuclear DNA double-strand breaks, phenotypes linked up-regulated levels specific messenger RNAs (mRNA). These findings place MARF1 as key regulator mammalian fertility through its integration oocyte mRNA homeostasis,...