A5048591919- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Muscle Physiology and Disorders
- Neurological disorders and treatments
- DNA Repair Mechanisms
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Fungal and yeast genetics research
- Ubiquitin and proteasome pathways
- Parkinson's Disease Mechanisms and Treatments
- Neuroscience and Neuropharmacology Research
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Hereditary Neurological Disorders
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- Renin-Angiotensin System Studies
- Eicosanoids and Hypertension Pharmacology
- Congenital heart defects research
- Cardiomyopathy and Myosin Studies
- Genomic variations and chromosomal abnormalities
- Coenzyme Q10 studies and effects
- Plant Genetic and Mutation Studies
- Cancer-related molecular mechanisms research
- Receptor Mechanisms and Signaling
Massachusetts General Hospital
2015-2024
Harvard University
2015-2024
Center for Genomic Science
2020
Center for Human Genetics
2008-2017
University of California, Davis
2015
California Institute for Regenerative Medicine
2015
Boston University
2014
Harvard University Press
2000-2012
Emory University
2000
New York University
2000
Lengthening a glutamine tract in huntingtin confers dominant attribute that initiates degeneration of striatal neurons Huntington's disease (HD). To identify pathways are candidates for the mutant protein's abnormal function, we compared cell lines established from wild-type and HdhQ111 knock-in embryos. Alternate versions full-length huntingtin, distinguished by epitope accessibility, were localized to different sets nuclear perinuclear organelles involved RNA biogenesis membrane...
Huntington's disease (HD) is caused by an expanded N-terminal glutamine tract that endows huntingtin with a striatal-selective structural property ultimately toxic to medium spiny neurons. In precise genetic models of juvenile HD, HdhQ92 and HdhQ111 knock-in mice, long polyglutamine segments change huntingtin's physical properties, producing HD-like in vivo correlates the striatum, including nuclear localization version full-length protein predominant neurons, subsequent formation inclusions...
The age of onset Huntington's disease (HD) is determined primarily by the length HD CAG repeat mutation, but also influenced other modifying factors. Delineating these modifiers a critical step towards developing validated therapeutic targets in patients. somatically unstable, undergoing progressive increases over time, particularly brain regions that are neurodegeneration. Here, we have explored hypothesis somatic instability itself modifier disease. Using small-pool PCR, quantified cortex...
The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of may therefore provide routes for therapies targeting the underlying mutation, an approach is likely applicable to other trinucleotide diseases. HdhQ111 mice exhibit higher levels HTT on a C57BL/6 genetic background (B6.HdhQ111) than 129 (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified single quantitative trait locus...
The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation somatic tissues. In subset male transmissions, larger occur produce extreme HD alleles that display instability and cause juvenile onset disorder. Initial efforts reproduce these features mouse model transgenic for exon 1 with 48 revealed only mild ( approximately 2% meioses). A...
Somatic instability of expanded HD CAG repeats that encode the polyglutamine tract in mutant huntingtin has been implicated striatal selectivity Huntington's disease (HD) pathology. Here Hdh(Q111) mice, we have tested whether a genetic background deficient Msh2, expected to eliminate unstable behavior 109 array inserted into murine gene, would alter timing or specificity dominant phenotype predicts late-onset neurodegeneration. Our analyses Hdh(Q111/+):Msh2(+/+) and Hdh(Q111/+): Msh2(-/-)...
Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in huntingtin protein. Full-length thought to be a predominant HEAT repeat α-solenoid, implying role as facilitator macromolecular complexes. Here we have investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex 2 (PRC2), suggested shared embryonic deficiency phenotypes. Analysis set full-length recombinant huntingtins, different regions,...
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expansion of an unstable CAG repeat in the coding sequence Huntingtin (HTT) gene. Instability affects both germline and somatic cells. Somatic instability increases with age tissue-specific. In particular, striatum, brain region that preferentially degenerates HD, highly unstable, whereas it rather stable disease-spared cerebellum. The mechanisms underlying age-dependence tissue-specificity remain obscure. Recent...
In Huntington's disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in striatum, suggesting that changes could modify process. Therefore, understanding mechanisms underlying tissue specificity of instability may provide novel routes to therapies. However progress this area has been hampered by lack sensitive high-throughput...
Huntington's disease (HD) is a dominantly inherited neurodegenerative caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely the size HTT repeat. However, emerging evidence strongly supports role for other genetic factors modifying pathogenesis driven mutant huntingtin. A recent genome-wide association analysis to discover modifiers provided initial modifier loci on chromosomes 8 and 15 suggestive locus chromosome 3....
The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into in humans, we performed comprehensive quantitative analyses ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset one juvenile-onset HD individual. We also assessed ATXN1 brain regions an individual with neurologically pathologically...
In Huntington's disease (HD), CAG repeats extend a glutamine tract in huntingtin to initiate the dominant loss of striatal neurons and chorea. Neuropathological changes include formation insoluble mutant N-terminal fragment, as nuclear/neuropil inclusions filter-trap amyloid, which may either participate process or be degradative by-product. young Hdh knock-in mice, CAGs that expand mouse childhood-onset HD lengths lead nuclear accumulation full-length later fragment. Here we report...
The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. of the HD allele in male intergenerational transmissions is reflected variability DNA from sperm carriers gene.In this study, we used a collection 112 DNAs gene-positive members large Venezuelan cohort investigate factors associated with instability. We confirm previous observations that length strongest predictor repeat-length sperm, but did not find any correlation between and...
The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT) exhibits age-dependent tissue-specific expansion that correlates with onset patients, implicating somatic as a modifier and potential therapeutic target. Somatic HTT is critically dependent on proteins mismatch repair (MMR) pathway. To gain further insight into mechanisms of relationship to process selectively vulnerable MSNs we have crossed knock-in mice (HdhQ111) carrying conditional (floxed) Msh2 allele D9-Cre...
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,...