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Huntingtin interactome reveals huntingtin role in regulation of double strand break DNA damage response (DSB/DDR), chromatin remodeling and RNA processing pathways.
bioRxiv
December 2024
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 5 South, Baltimore, MD21287.
Huntington's Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by a CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of HD cellular pathogenesis and cellular functions of the normal and mutant HTT proteins are still not completely understood. HTT protein has numerous interaction partners, and it likely provides a scaffold for assembly of multiprotein complexes many of which may be altered in HD.
View Article and Find Full Text PDFIn vivo self-assembled siRNAs within small extracellular vesicles attenuate LRRK2-induced neurodegeneration in Parkinson's disease models.
J Control Release
January 2025
Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China; The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu 213003, China. Electronic address:
Rationale: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene play an important role in Parkinson's disease (PD) pathogenesis, and downregulation of LRRK2 has become a promising therapy for PD. Here, we developed a synthetic biology strategy for the self-assembly and delivery of small interfering RNAs (siRNAs) of LRRK2 into the substantia nigra via small extracellular vesicles (sEVs) using a genetic circuit (in the form of naked DNA plasmid) to attenuate PD-like phenotypes in mouse model.
Methods: We generated the genetic circuit encoding both a neuron-targeting rabies virus glycoprotein (RVG) tag and a LRRK2 siRNA under the control of a cytomegalovirus (CMV) promoter, and assessed its therapeutic effects using LRRK2 mouse models of PD.
Retrospective observational study of safety, performance, and duration of use of battery-powered intraosseous access device in pediatric patients.
SAGE Open Med
December 2024
Teleflex Incorporated, Morrisville, NC, USA.
Background: To demonstrate the safety and performance of the Arrow EZ-IO Intraosseous Vascular Access System, particularly in the pediatric patient population, a retrospective observational study was conducted in 2021 and 2022.
Methods: Following study design, IRB approval, and investigator selection, data were collected for all patients needing intraosseous access-adult and pediatric. The primary endpoint was the success rate for achieving intraosseous access; the secondary endpoint was the rate of adverse events.
Roscovitine, a CDK Inhibitor, Reduced Neuronal Toxicity of mHTT by Targeting HTT Phosphorylation at S1181 and S1201 In Vitro.
Int J Mol Sci
November 2024
Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Article Synopsis
- * Research has focused on post-translational modifications of the HTT protein, with findings showing that certain modifications can reduce the toxicity of the mutant protein in cell and animal models.
- * A study identified cyclin-dependent kinases (CDKs) that influence the phosphorylation of specific serine sites on HTT, and the CDK inhibitor roscovitine demonstrated protective effects against mutant HTT toxicity in HD mice, highlighting its potential as a pre-clinical therapeutic.
Structural MRI Correlates of Anosognosia in Huntington's Disease.
J Huntingtons Dis
September 2024
Departments of Neurology and Division of Neurobiology, Department of Psychiatry JHUSOM, Baltimore, MD, USA.
Article Synopsis
- Anosognosia, or a lack of awareness of symptoms, is prevalent in Huntington's disease (HD), but researchers have not fully understood its neuroanatomical causes.
- The study utilized MRI data from 570 HD participants to analyze correlations between brain structures and the severity of anosognosia, measured through discrepancies in scores between patients and their caregivers.
- Findings revealed that the volume of the globus pallidus, along with other brain regions, significantly correlates with anosognosia, indicating that neurodegeneration in both cortical and subcortical areas, especially the globus pallidus, plays a crucial role in this condition.
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