A5036479389- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Muscle Physiology and Disorders
- Neurological disorders and treatments
- RNA Research and Splicing
- Neuroscience and Neuropharmacology Research
- Ubiquitin and proteasome pathways
- Fungal and yeast genetics research
- Prion Diseases and Protein Misfolding
- RNA regulation and disease
- Neurogenetic and Muscular Disorders Research
- Endoplasmic Reticulum Stress and Disease
- Single-cell and spatial transcriptomics
- Neurotransmitter Receptor Influence on Behavior
- RNA modifications and cancer
- DNA Repair Mechanisms
- Trace Elements in Health
- Genetics and Neurodevelopmental Disorders
- Neurological diseases and metabolism
- Amyotrophic Lateral Sclerosis Research
- Virus-based gene therapy research
- Neurological and metabolic disorders
- Hereditary Neurological Disorders
- Receptor Mechanisms and Signaling
- Robotics and Automated Systems
Western Washington University
2016-2025
University of Washington
2023-2025
Seattle University
2023-2024
Center for Human Genetics
2015-2017
Harvard University
2015-2017
Massachusetts General Hospital
2014-2017
University of British Columbia
2006-2011
Child and Family Research Institute
2006-2011
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion in the huntingtin gene (HTT) that results a toxic gain of function mutant protein (mHTT). Reducing expression mHTT therefore attractive therapy for HD. However, wild-type HTT essential development and has critical roles maintaining neuronal health. Therapies HD reduce may generate unintended negative consequences. We have identified single-nucleotide polymorphism (SNP) targets human population...
Huntington disease is a genetic neurodegenerative disorder that produces motor, neuropsychiatric, and cognitive deficits caused by an abnormal expansion of the CAG tract in huntingtin (htt) gene. In humans, mutated htt induces preferential loss medium spiny neurons striatum and, to lesser extent, cortical as progresses. The mechanisms causing these degenerative changes remain unclear, but they may involve synaptic dysregulation. We examined activity corticostriatal pathway using combination...
Brain cholesterol, which is synthesized locally, a major component of myelin and cell membranes participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, synaptogenesis. Here we show that brain cholesterol biosynthesis reduced multiple transgenic knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits mutant astrocytes. Mice carrying progressively increased number CAG repeats more evident reduction biosynthesis....
Huntington disease (HD) is a dominant, genetic neurodegenerative characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there currently no disease-modifying therapy. HD caused the expansion CAG tract in huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, significant evidence that muHTT lowering would be therapeutically efficacious. However, wild-type (wtHTT) serves vital making allele-specific...
Prion disease is a fatal, incurable neurodegenerative of humans and other mammals caused by conversion cellular prion protein (PrPC) into self-propagating neurotoxic conformer (prions; PrPSc). Strong genetic proofs concept support lowering PrP expression as therapeutic strategy. Antisense oligonucleotides (ASOs) can provide practical route to 1 target mRNA in the brain, but their development for has been hindered 3 unresolved issues from prior work: uncertainty about mechanism action,...
Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration resulting motor dysfunction, cognitive decline, psychiatric disturbances. Currently, there no altering treatment, symptomatic therapy has limited benefit. pathogenesis of HD complicated multiple pathways are compromised. Addressing problem at its genetic root suppressing expression promising...
Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset intracerebrally prion-infected mice both prophylactic delayed dosing paradigms. Here, we examine efficacy this approach across diverse paradigms, varying dose regimen, strain, treatment timepoint, examining symptomatic, survival, biomarker readouts....
Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative caused by CAG in
Huntington's disease, one of more than 50 inherited repeat expansion disorders1, is a dominantly neurodegenerative disease caused by CAG in HTT2. Inherited length the primary determinant age onset, with human genetic studies underscoring that driven length-dependent propensity to further expand brain3–9. Routes slowing somatic expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably mismatch pathway, modify mouse models10. To identify novel...
Proteolysis of mutant huntingtin is crucial to the development Huntington disease (HD). Specifically preventing proteolysis at capase-6 (C6) consensus sequence amino acid 586 prevents behavioural, motor and neuropathological features in a mouse model HD. However, mechanism underlying selective toxicity cleavage event currently unknown. We have examined subcellular localization different caspase proteolytic fragments using neo-epitope antibodies. Our data suggest that nucleus primary site htt...
Our recent analyses of the cholesterol biosynthetic pathway in Huntington's disease (HD) cells, R6/2 huntingtin-fragment mouse model HD as well human tissues have provided first evidence altered activity this genetically identifiable samples. Here we report that these changes also occur full-length-huntingtin YAC128 (yeast artificial chromosome) model, which shows a consistent reduction or levels multiple components cholesterogenic pathway. We show phenotype is progressive and specific for...
Silencing the mutant huntingtin gene (muHTT) is a direct and simple therapeutic strategy for treatment of Huntington disease (HD) in principle. However, targeting HD mutation presents challenges because it an expansion common genetic element (a CAG tract) that found throughout genome. Moreover, HTT protein important neuronal health life, silencing strategies also reduce wild-type allele may not be well tolerated during long-term HD. Several are development target sites outside expansion,...
Huntington disease (HD) is caused by polyglutamine expansion in the huntingtin (HTT) protein. Huntingtin-interacting protein 14 (HIP14), one of 23 DHHC domain-containing palmitoyl acyl transferases (PATs), binds to HTT and robustly palmitoylates at cysteine 214. Mutant exhibits reduced palmitoylation interaction with HIP14, contributing neuronal dysfunction associated HD. In this study, we confirmed that, among PATs, HIP14 its homolog DHHC-13 (HIP14L) are two major PATs that palmitoylate...
Article26 March 2018Open Access Transparent process Transcriptional regulatory networks underlying gene expression changes in Huntington's disease Seth A Ament Institute for Systems Biology, Seattle, WA, USA Genome Sciences and Department of Psychiatry, University Maryland School Medicine, Baltimore, MD, Search more papers by this author Jocelynn R Pearl Molecular & Cellular Biology Graduate Program, Washington, Altius Biomedical Sciences, Jeffrey P Cantle Behavioral Neuroscience Psychology,...
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by trinucleotide expansion in exon 1 of the huntingtin ( HTT ) gene. Cell death HD occurs primarily striatal medium spiny neurons (MSNs), but involvement specific MSN subtypes and other cell types remains poorly understood. To gain insight into type-specific processes, we studied nuclear transcriptomes 4524 cells from striatum genetically precise knock-in mouse model mutation, Htt Q175 /+ , wild-type...
Abstract Huntington’s disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form HTT. Both wildtype and disease-state HTT hetero-dimer with HAP40 unknown functional relevance. We demonstrate vivo cell models that cellular abundance are coupled. Integrating data 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, modeling, we provide near-atomic-level view HTT, its...
Huntington's disease is a dominantly inherited neurodegenerative caused by the expansion of CAG repeat in HTT gene. In addition to length expansion, factors such as genetic background have been shown contribute age at onset neurological symptoms. A central challenge understanding progression that leads from HD mutation massive cell death striatum ability characterize subtle and early functional consequences longitudinally. We used dense time course sampling between 4 20 postnatal weeks...