A5039890109- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- RNA Interference and Gene Delivery
- Muscle Physiology and Disorders
- Neurological disorders and treatments
- RNA Research and Splicing
- Advanced biosensing and bioanalysis techniques
- Adrenal and Paraganglionic Tumors
- Neuropeptides and Animal Physiology
- Cancer, Hypoxia, and Metabolism
- MicroRNA in disease regulation
- Neuroscience and Neuropharmacology Research
- CRISPR and Genetic Engineering
- Pituitary Gland Disorders and Treatments
- Extracellular vesicles in disease
- Hormonal Regulation and Hypertension
- Pain Mechanisms and Treatments
- Circadian rhythm and melatonin
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Virus-based gene therapy research
- DNA and Nucleic Acid Chemistry
- Growth Hormone and Insulin-like Growth Factors
- Photoreceptor and optogenetics research
- Regulation of Appetite and Obesity
University of Massachusetts Chan Medical School
2016-2025
Massachusetts Academy of Math and Science
2024
Mount Sinai Medical Center
1980-2015
Howard Hughes Medical Institute
2009
Memorial Medical Center
2005
UMass Memorial Medical Center
2005
Massachusetts General Hospital
1981-2001
Harvard University
1982-1998
University College London
1997
Guy's Hospital
1997
The cause of neurodegeneration in Huntington's disease (HD) is unknown. Patients with HD have an expanded NH 2 -terminal polyglutamine region huntingtin. An fragment mutant huntingtin was localized to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs) the cortex striatum, which are affected HD, length influenced extent accumulation these structures. Ubiquitin also found NIIs DNs, suggests that abnormal targeted for proteolysis but resistant removal. aggregation may be part...
Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are explored for use in diagnostics, therapeutics drug delivery. However, little is known about the relationship of protein lipid composition EVs their source cells. Here, we report high-resolution lipidomic proteomic analyses MVs derived by differential ultracentrifugation from 3 different cell types: U87 glioblastoma cells, Huh7 hepatocellular carcinoma cells human bone marrow-derived mesenchymal stem (MSCs). We...
An expansion of polyglutamines in the N terminus huntingtin causes Huntington9s disease (HD) and results accrual mutant protein nucleus cytoplasm affected neurons. How neurons to die is unclear, but some recent observations suggest that an autophagic process may occur. We showed previously markedly accumulates endosomal–lysosomal organelles HD and, when exogenously expressed clonal striatal neurons, appears cytoplasmic vacuoles causing cells shrink. Here we show huntingtin-enriched formed...
Microglia may contribute to cell death in neurodegenerative diseases. We studied the activation of microglia affected regions Huntington disease (HD) brain by localizing thymosin β-4 (Tβ4), which is increased reactive microglia. Activated appeared neostriatum, cortex, and globus pallidus adjoining white matter HD brain, but not control brain. In striatum occurred all grades pathology, accumulated with increasing grade, grew density relation degree neuronal loss. The predominant morphology...
Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for treatment neurological disorders, such as Huntington's disease. Small, endogenous vesicles known exosomes have potential act delivery vehicles, but robust and scalable methods loading RNA therapeutic cargo into are lacking. Here, we show that hydrophobically modified small interfering RNAs (hsiRNAs) efficiently load upon co-incubation, without altering vesicle size distribution or...
Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of CAG repeat in the huntingtin (Htt) gene. HD autosomal dominant and, theory, amenable to therapeutic RNA silencing. We introduced cholesterol-conjugated small interfering duplexes (cc-siRNA) targeting human Htt mRNA (siRNA-Htt) into mouse striata that also received adeno-associated virus containing either expanded (100 CAG) or wild-type (18 cDNA encoding 1-400. Adeno-associated delivery striatum and overlying...
Exosomes can deliver therapeutic RNAs to neurons. The composition and the safety profile of exosomes depend on type exosome-producing cell. Mesenchymal stem cells are considered be an attractive cell for exosome production. However, scalable methods isolate manufacture from mesenchymal lacking, a limitation clinical translation technology. We evaluate different sources find that umbilical cord-derived produce highest yield. To optimize production, we cultivate in microcarrier-based...
CRISPR-Cas systems are a diverse family of RNA-protein complexes in bacteria that target foreign DNA sequences for cleavage. Derivatives these have been engineered to cleave specific depending on the sequence CRISPR-derived guide RNA (gRNA) and source Cas9 protein. Important considerations design gRNAs maximize aimed activity at desired site while minimizing off-target Because rapid advances understanding existing CRISPR-Cas9-derived RNA-guided nucleases development novel nuclease systems,...
The Huntington's disease (HD) mutation is a polyglutamine expansion in the N-terminal region of huntingtin (N-htt). How neurons die HD unclear. Mutant N-htt aggregates brain; expression mutant vitro causes cell death. Other studies show that proteolysis by caspase 3 could be important regulating function, but there has been no direct evidence for 3-cleaved fragments brain. Here, we consistent with size produced cleavage are resident cortex, striatum, and cerebellum normal adult onset brain...
Abstract The immunohistochemical localization of huntingtin was examined in the Huntington's disease (HD) brain with an antibody that recognizes wild‐type and mutant proteins. Neuronal staining reduced areas HD striatum depleted medium‐sized neurons; large striatal neurons, which are spared HD, retained normal levels expression. labeling markedly both segments globus pallidus including brains minimal loss pallidal neurons. In some cortical neurons looking morphology, associated punctate...
Neuronal intranuclear inclusions are found in the brains of patients with Huntington's disease and form from polyglutamine-expanded N-terminal region mutant huntingtin. To explore properties their involvement cell death, mouse clonal striatal cells were transiently transfected truncated full-length human wild-type huntingtin cDNAs. Both normal proteins localized cytoplasm, infrequently, dispersed perinuclear vacuoles. Only formed nuclear cytoplasmic inclusions, which increased polyglutamine...
Neurons in Huntington's disease exhibit selective morphological and subcellular alterations the striatum cortex. The link between these neuronal changes behavioral abnormalities is unclear. We investigated relationships essential that predict motor impairment possible involvement of corticostriatal pathway developing phenotypes. therefore generated heterozygote mice expressing N-terminal one-third huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. HD exhibited...
Mammalian circadian rhythmicity is endogenously generated by a pacemaker in the suprachiasmatic nuclei and precisely entrained to 24-hr day/night cycle periodic environmental light cues. We show that alters immunoreactive levels of transcriptional regulatory protein, Fos, albino rats. Photic regulation Fos immunoreactivity does not occur other retino-recipient brain areas except for intergeniculate leaflet, which appears be involved mediating some complex effects on expressed rhythms. Our...
Huntingtin is a protein of unknown function that contains polyglutamine tract, which expanded in patients with Huntington's disease (HD). We investigated the localization and potential for huntingtin nucleus. In human fibroblasts from normal HD patients, localized diffusely nucleus subnuclear compartments identified as speckles, promyelocytic leukemia bodies, nucleoli. Huntingtin-positive nuclear bodies redistributed after treatment sodium butyrate. By Western blot, purified nuclei had low...
Small interfering RNAs (siRNAs), the guides that direct RNA interference (RNAi), provide a powerful tool to reduce expression of single gene in human cells. Ideally, dominant, gain-of-function diseases could be treated using siRNAs specifically silence mutant disease allele, while leaving wild-type allele unperturbed. Previous reports suggest can designed with nucleotide specificity, but no rational basis for design discrimination has been proposed. We systematically identified discriminate...
D1 dopamine receptor localization was examined by immunohistochemistry using a polyclonal anti-peptide antibody which (i) immunoprecipitated protein fragment encoded cDNA and (ii) on Western blots of solubilized striatal hippocampal membranes recognized two proteins approximately 50 kDa 75 kDa, corresponding to reported sizes proteins. Immunoreactivity overlapped with dopamine-containing pathways, patterns binding, mRNA expression. Staining concentrated in prefrontal, cingulate, parietal,...
Osteocalcin, a bone-specific protein and marker of the mature osteoblast, is expressed only in nonproliferating osteoblasts mineralizing extracellular matrix, while type I collagen proliferating cells. The nuclear proteins encoded by c-fos c-jun protooncogenes are during proliferation period osteoblast phenotype development. We present evidence that AP-1 (HeLa cell-activating 1) sites residing within two promoter elements osteocalcin gene bind Fos-Jun complex: box (OC box; nucleotides -99 to...