A5035352402- Amyotrophic Lateral Sclerosis Research
- Genetic Neurodegenerative Diseases
- Neurogenetic and Muscular Disorders Research
- Autophagy in Disease and Therapy
- RNA Research and Splicing
- Endoplasmic Reticulum Stress and Disease
- Mitochondrial Function and Pathology
- Adenosine and Purinergic Signaling
- Nerve injury and regeneration
- RNA modifications and cancer
- DNA Repair Mechanisms
- Spinal Cord Injury Research
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Microtubule and mitosis dynamics
- Neuroscience of respiration and sleep
- Telomeres, Telomerase, and Senescence
- Parkinson's Disease Mechanisms and Treatments
- Genetic Syndromes and Imprinting
- Biochemical Acid Research Studies
- Neurogenesis and neuroplasticity mechanisms
- Cellular transport and secretion
- CRISPR and Genetic Engineering
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Neurological diseases and metabolism
University of Utah
2019-2025
Oregon State University
2011-2013
Institut Pasteur
2013
Universidad de la República de Uruguay
2010-2012
Institut Pasteur de Montevideo
2008-2011
Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase-1 (SOD1) may injury ALS. Here, we provide evidence mitochondrial SOD1 G93A rat causes induce apoptosis neurons. Mitochondria from displayed a defective respiratory function, including decreased oxygen consumption, lack ADP-dependent control, membrane potential. Protein...
During pathology of the nervous system, increased extracellular ATP acts both as a cytotoxic factor and pro-inflammatory mediator through P2X(7) receptors. In animal models amyotrophic lateral sclerosis (ALS), astrocytes expressing superoxide dismutase 1 (SOD1G93A) mutations display neuroinflammatory phenotype contribute to disease progression motor neuron death. Here we studied role acting receptors an initiator neurotoxic that leads astrocyte-mediated death in non-transgenic SOD1G93A...
Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing ALS-linked SOD1(G93A) mutation display a decreased mitochondrial respiratory capacity associated phenotypic changes cause them induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating critical role mitochondria neurotoxic phenotype. However, it presently unknown whether drugs...
Mutations in the ATXN2 gene (CAG expansions ≥32 repeats) can be a rare cause of Parkinson's disease and amyotrophic lateral sclerosis (ALS). We recently reported that stress granule (SG) protein Staufen1 (STAU1) was overabundant neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, ALS-TDP-43 fibroblasts, provided link between SG formation autophagy. aimed to test if STAU1 overabundance has role pathogenesis other diseases.With multiple patient-derived...
The P2X7 receptor/channel responds to extracellular ATP and is associated with neuronal death neuroinflammation in spinal cord injury amyotrophic lateral sclerosis. Whether activation of directly causes motor neuron unknown. We found that cultured neurons isolated from embryonic rat express underwent caspase-dependent apoptosis when exposed exceptionally low concentrations the agonist 2'(3')-O-(4-Benzoylbenzoyl)-ATP. inhibitors BBG, oATP, KN-62 prevented...
Abstract Staufen-1 (STAU1) is an RNA-binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations presenilin1 (PSEN1), microtubule-associated tau ( MAPT ), huntingtin HTT TAR DNA-binding protein-43 gene TARDBP or C9orf72. We previously reported elevations STAU1 determine autophagy defects and its knockdown protective models of several diseases. Additional functional consequences overabundance, however, have not been...
Objective The mechanistic target of rapamycin (mTOR) kinase is one the master coordinators cellular stress responses, regulating metabolism, autophagy, and apoptosis. We recently reported that staufen1 (STAU1), a granule (SG) protein, was overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis, frontotemporal degeneration, Huntington's, Alzheimer's, Parkinson's diseases as well animal models, patient tissues. STAU1...
Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive polyglutamine (polyQ) disease, is caused by CAG repeat expansion ataxin-2 (ATXN2) gene. In this study, we determined miRNA transcriptomes SCA2-BAC-ATXN2[Q72] transgenic mice.
Abstract The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen SCA2, CAG repeat expansions long normal range increase ALS risk. Also, lowering expression TDP-43 mice prolongs their survival. Here we investigated relationship with dysfunction vivo by comparing spinal cord (SC) transcriptomes reported from SOD1 patients those SCA2...
Staufen2 (STAU2) is an RNA binding protein that controls mRNA trafficking and expression. Previously, we showed its paralog Staufen1 (STAU1) was overabundant in cellular mouse models of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) patient spinal cord. Here investigated features STAU2 might parallel STAU1. protein, but not mRNA, spinocerebellar ataxia type 2 (SCA2), ALS/frontotemporal dementia (FTD) fibroblasts, ALS cord tissues, central nervous system (CNS) tissues from...
The Nogo-66 receptor (NgR) plays a critical role in restricting axon regeneration the central nervous system. This inhibitory action is part mediated by neuronal complex containing p75NTR, multifunctional also well known to trigger cell death upon binding neurotrophins such as NGF. In present study, we show that Pep4 and NEP1–40, which are two peptides derived from sequence modulate NgR-mediated neurite outgrowth inhibition, prevent NGF-stimulated p75NTR-dependent of cultured embryonic motor...
CAG repeat expansions in the ATXN2 (ataxin-2) gene can cause autosomal dominant disorder spinocerebellar ataxia type 2 (SCA2) as well increase risk of ALS. Abnormal molecular, motor, and neurophysiological phenotypes SCA2 mouse models are normalized by lowering transcription, reduction nonmutant Atxn2 expression has been shown to life span mice overexpressing TDP-43 (transactive response DNA-binding protein 43 kDa) ALS protein, demonstrating potential benefits targeting transcription humans....
Accumulation of α-synuclein is a main underlying pathological feature Parkinson's disease and α-synucleinopathies, for which lowering expression the gene (SNCA) potential therapeutic avenue. Using cell-based luciferase reporter SNCA we performed quantitative high-throughput screen 155,885 compounds identified A-443654, an inhibitor multiple functional kinase AKT, as potent SNCA. HEK-293 cells with CAG repeat expanded ATXN2 (ATXN2-Q58 cells) have increased levels α-synuclein. We found that...
Telomeres are nucleotide repeat sequences located at the end of chromosomes that protect them from degradation and maintain chromosomal stability. shorten with each cell division; hence telomere length is associated aging longevity. Numerous lifestyle factors have been identified impact rate shortening; high vitamin consumption has longer length, whereas oxidative stress shortening. In this paper, we sought to determine if a multivitamin mixture containing both vitamins blend polyphenolic...
Abstract The shaker rat carries a naturally occurring mutation leading to progressive ataxia characterized by Purkinje cell (PC) loss. We previously reported on fine-mapping the locus long arm of X chromosome. In this work, we sought identify mutated gene underlying phenotype and confirm its identity functional complementation. fine-mapped candidate region analyzed cerebellar transcriptomes, identifying XM_217630.9 (Slc9a6):c.[191_195delinsA] variant in Slc9a6 that segregated with disease....
Abstract Despite linkage to 16q in 1996, the mutation for spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, escaped detection 25 years. Using long- read PacBio-HiFi ONT-Nanopre sequencing bioinformatic analysis, we identified expansion of GGC DNA repeat >85% GC-rich region exon 10 ZFHX3 gene coding poly-glycine (polyG). In total 15 nuclear families from Utah 9 Europe, was expanded >40 repeats SCA4 patients accompanied by significant phenotypic variation...
Abstract Objective The mechanistic target of rapamycin (mTOR) kinase is one the master coordinators cellular stress responses, regulating metabolism, autophagy, and apoptosis. We recently reported that Staufen1 (STAU1), a granule (SG) protein, was overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis, frontotemporal degeneration, Huntington’s, Alzheimer’s, Parkinson’s diseases as well animal models, patient tissues. STAU1...
ABSTRACT Staufen1 (STAU1) is a multifunctional RNA binding protein that controls mRNA degradation and subcellular localization. STAU1 interacts with the ATXN2 protein, polyglutamine expanded in spinocerebellar ataxia type 2 (SCA2). We previously showed elevated aggregated cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) ALS mouse models. also found reduction of abundance vivo by genetic interaction improved motor behavior an model, normalized levels several SCA2-related...
Abstract Background Christianson syndrome (CS) is an x-linked recessive neurodevelopmental and neurodegenerative condition characterized by severe intellectual disability, cerebellar degeneration, ataxia, epilepsy. Mutations to the SLC9A6 gene encoding NHE6 are responsible for CS, we recently demonstrated that a mutation rat Slc9a6 causes similar phenotype in spontaneous shaker model, which exhibits degeneration with motor dysfunction. In previous work, used PhP.eB-L7-Slc9a6-GFP...
Abstract Staufen-1 (STAU1) is an RNA binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations presenilin1 (PSEN1), microtubule associated tau ( MAPT ), huntingtin HTT TAR DNA-binding protein-43 gene TARDBP ) or C9orf72. We previously reported elevations STAU1 determine autophagy defects. Additional functional consequences of overabundance, however, have not been investigated. studied the role chronic activation Unfolded...
Abstract Background The shaker rat carries a naturally occurring mutation leading to progressive ataxia characterized by Purkinje cell (PC) loss. We previously reported on fine-mapping the locus long arm of X chromosome. In this work, we sought identify mutated gene underlying phenotype and confirm its identity functional complementation. Methods fine-mapped candidate region analyzed cerebellar transcriptomes deleterious variants. generated an adeno-associated virus (AAV) targeting solute...