A5024930123- Genetics and Neurodevelopmental Disorders
- Histone Deacetylase Inhibitors Research
- Nerve injury and regeneration
- Lysosomal Storage Disorders Research
- Alzheimer's disease research and treatments
- Autism Spectrum Disorder Research
- Parkinson's Disease Mechanisms and Treatments
- Muscle Physiology and Disorders
- Ubiquitin and proteasome pathways
- Atherosclerosis and Cardiovascular Diseases
- Autophagy in Disease and Therapy
- DNA Repair Mechanisms
- RNA Research and Splicing
- Endoplasmic Reticulum Stress and Disease
- Bacterial Genetics and Biotechnology
- Mitochondrial Function and Pathology
- DNA and Nucleic Acid Chemistry
- Nuclear Structure and Function
- Genomics and Chromatin Dynamics
- Genetic Neurodegenerative Diseases
- Nuclear Receptors and Signaling
- S100 Proteins and Annexins
Rapt Therapeutics (United States)
2024
Brigham and Women's Hospital
2015-2021
Harvard University
2015-2021
The University of Texas at Dallas
2011-2013
Institute of Molecular and Cell Biology
2012
Although it is well established that pharmacological inhibitors of classical histone deacetylases (HDACs) are protective in various vivo models neurodegenerative disease, the identity neurotoxic HDAC(s) these target to exert their effects has not been resolved. We find HDAC3 a protein with strong activity. Forced expression induces death otherwise healthy rat cerebellar granule neurons, whereas shRNA-mediated suppression its protects against low-potassium-induced neuronal death. also...
Both neuroprotective and neurotoxic roles have previously been described for histone deacetylase-1 (HDAC1). Here we report that HDAC1 expression is elevated in vulnerable brain regions of two mouse models neurodegeneration, the R6/2 model Huntington disease Ca2+/calmodulin-dependent protein kinase (CaMK)/p25 double-transgenic tauopathic degeneration, suggesting a role promoting neuronal death. Indeed, elevating by ectopic promotes death otherwise healthy cerebellar granule neurons cortical...
The methyl-CpG binding protein 2 (MeCP2) is a widely expressed protein, the mutations of which cause Rett syndrome. level MeCP2 highest in brain where it selectively mature neurons. Its functions postmitotic neurons are not known. gene alternatively spliced to generate two proteins with different N termini, designated as MeCP2-e1 and MeCP2-e2 . physiological significance these isoforms has been elucidated, generally assumed they functionally equivalent. We report that cultured cerebellar...
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson disease. Genetics and neuropathology link disease with microtubule-binding protein tau, but mechanism action LRRK2 mutations molecular connection between tau unclear. Here, we investigate interaction LRRK Drosophila mouse models tauopathy. We find that either increasing or decreasing level fly Lrrk enhances neurotoxicity, which is further exacerbated by expressing dominantly acting...
Huntington9s disease (HD) is caused by a polyglutamine expansion within the huntingtin (Htt) protein. Both loss of function normal Htt and gain toxic polyglutamine-expanded mutant protein have been proposed to be responsible for HD, although molecular mechanisms involved are unclear. We show that neuroprotective in both HD-related unrelated model systems. Neuroprotection mediated its sequestration histone deacetylase-3 (HDAC3), known promote neuronal death. In contrast Htt, interacts poorly...
The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which caused by mutations tau. In vitro , FTDP-17 mutant versions of can reduce increase the aggregation tau, but mechanism these promote disease vivo not clear. Here we take a combined biochemical modeling approach define functional properties driving neurotoxicity . We express wild-type human five forms...
The Cre-recombination system has become an important tool for genetic manipulation of higher organisms and a model site-specific DNA-recombination mechanisms employed by the λ-Int superfamily recombinases. We report novel quantitative approach characterizing probability DNA-loop formation in solution using time-dependent ensemble Förster resonance energy transfer measurements intra- inter-molecular kinetics. Our method uses innovative technique incorporating multiple covalent modifications...
Abstract Background Mutations in LRRK2 are the most common cause of familial Parkinson’s disease and typically context abnormal aggregation deposition α-synuclein within affected brain tissue. Methods We combine genetic analysis Lrrk-associated toxicity a penetrant Drosophila model wild type human neurotoxicity with biochemical analyses modeling neurons transgenic mouse models. Results demonstrate that Lrrk interact to promote neuronal degeneration through convergent effects on actin...
Background: Apolipoprotein C-III (APOC3) is a key regulator of lipid metabolism that inhibits the catabolism and clearance triglyceride (TG)-rich lipoproteins in blood. Loss-of-function APOC3 variants are associated with significantly lower TG levels reduced risk heart disease, underscoring potential inactivation as therapeutic strategy for patients familial chylomicronemia syndrome (FCS) severe hypertriglyceridemia (SHTG). Here, we developed STX-1400 lead molecules novel investigational...
Background: CRISPR-based genetic medicines offer a promising “one and done” approach to improve cardiovascular health by lowering LDL-C. We performed comparative analysis of different gene editing approaches targeting PCSK9 for potent safe Based on our findings, we engineered two investigational products using novel CRISPR-CasX platform: editor an epigenetic editor. demonstrated the efficacy safety these agents in vivo, including non-human primates (NHPs). Methods: CasX-based molecules....