A5000410225- Genetic Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Mitochondrial Function and Pathology
- Cholesterol and Lipid Metabolism
- Neurological disorders and treatments
- Nanoparticle-Based Drug Delivery
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA regulation and disease
- Neuroinflammation and Neurodegeneration Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Attention Deficit Hyperactivity Disorder
- Cellular transport and secretion
- Cell Image Analysis Techniques
- Diet, Metabolism, and Disease
- Metabolism and Genetic Disorders
Istituto Nazionale Genetica Molecolare
2019-2023
University of Milan
2018-2023
Abstract Brain cholesterol is produced mainly by astrocytes and important for neuronal function. Its biosynthesis severely reduced in mouse models of Huntington’s disease. One possible mechanism a diminished nuclear translocation the transcription factor sterol regulatory element-binding protein 2 (SREBP2) and, consequently, activation SREBP2-controlled genes pathway. Here we evaluated efficacy gene therapy based on unilateral intra-striatal injection recombinant adeno-associated virus 2/5...
The current pharmacological treatment of Huntington's disease (HD) is palliative, and therapies to restore functions in patients are needed. One the pathways affected HD involves brain cholesterol (Chol) synthesis, which essential for optimal synaptic transmission. Recently, it was reported that a mouse model, delivery exogenous Chol with brain-permeable nanoparticles protected animals from cognitive decline rescued communication, indicating as therapeutic candidate. We examined whether...
A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected the HD mouse brain from pre-symptomatic stages, leading to diminished synthesis, particularly striatum. In addition, systemic injection cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function a transgenic model HD. To identify an appropriate treatment regimen gain mechanistic insights into beneficial...
Synaptic dysfunction and cognitive decline in Huntington's disease (HD) involve hyperactive A disintegrin metalloproteinase domain-containing protein 10 (ADAM10). To identify the molecular mechanisms through which ADAM10 is associated with synaptic HD, we performed an immunoaffinity purification-mass spectrometry (IP-MS) study of endogenous brains wild-type HD mice. We found that proteins implicated synapse organization, plasticity, vesicle organelles trafficking interact ADAM10, suggesting...
There are numerous studies showing a reduction in cholesterol biosynthesis the brain of different HD animal models since pre-symptomatic stages, with striatum being more affected compared to other tissues (Valenza et al., 2005; 2007; 2010; Shankaran 2017). Abnormalities homeostasis also present patients: specific metabolite 24-hydroxy-cholesterol (24OHC) is progressively reduced plasma patients and pre-HD manifesting individuals who close onset disease (Leoni 2008; 2013). On hand, we...
Abstract A variety of pathophysiological mechanisms are implicated in Huntington’s disease (HD). Among them, reduced cholesterol biosynthesis has been detected the HD mouse brain from pre-symptomatic stages, leading to diminished synthesis, particularly striatum. In addition, systemic injection cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function a transgenic model HD. To identify an appropriate treatment regimen gain mechanistic insights into...
Abstract Evidence that Huntington’s disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies increase its level of rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested long-term efficacy chronic administration slowly zQ175DN knock-in HD mice preventing (“early treatment”) or reversing (“late symptoms. To do this used most advanced formulation loaded brain-permeable nanoparticles (NPs), termed...
<h3>Objectives</h3> Brain cholesterol is produced in situ and its turn-over ensured by the conversion into 24S-hydroxycholesterol (24-OHC) which can cross blood-brain barrier. biosynthesis was shown to be reduced murine models of Huntington's disease (HD) 24-OHC plasma concentrations were found HD patients. We aimed investigate longitudinal changes correlate levels with progression, basal ganglia MRI volumes, neurofilament concentrations. <h3>Participants Methods</h3> conducted a 2-year...
<h3>Background</h3> ADAM10 is a major protease of the human brain and regulates strength activity glutamatergic synapse by cleaving large repertoire synaptic substrates. In Huntington's Disease (HD), active accumulates at postsynaptic density causes proteolysis cell adhesion protein Ncadherin, loss excitatory contacts cognitive decline. <h3>Aims Methods</h3> To identify molecular mechanisms through which associated with dysfunction in HD, we performed system-level study interactors HD mice....
Brain is most cholesterol-rich organ in the body. Since cholesterol does not cross blood brain barrier, its metabolism provided situ by astrocytes and neurons, it crucial for maintaining sterol levels neuronal integrity function. Recent studies have shown that of precursors metabolites are lower brains animal models Huntington's disease (HD) while reduced catabolite detected plasma patients. In this study, we introduce a novel analytical method designed to fulfil complex requirements...
Abstract Brain cholesterol is produced mainly by astrocytes and important for neuronal function. Its biosynthesis severely reduced in mouse models of Huntington’s Disease (HD). One possible mechanism a diminished nuclear translocation the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, activation SREBP-controlled genes pathway. Here we evaluated efficacy gene therapy based on unilateral intra-striatal injection recombinant adeno-associated virus...
Abstract Supplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient biosynthesis. However, delivering to the challenging due bloodbrain barrier (BBB), which prevents it from reaching striatum, especially, with therapeutically relevant doses. Here we describe distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made PLGA were...
<h3>Background</h3> Huntington's disease (HD) is associated with reduced synthesis of brain cholesterol (chol) and mounting evidence highlights the concept that strategies aimed at delivering chol to beneficial in HD. More recently, we demonstrated systemic administration most advanced formulation brain-permeable chol-loaded nanoparticles (hybrid-g7-NPs-chol) prevents cognitive decline ameliorates some motor defects fast-progressing R6/2 mouse model. <h3>Aims Methods</h3> Here employed...
<h3>Background</h3> Cholesterol (Chol), an essential molecule for brain function, is produced locally in the as blood-brain barrier (BBB) prevents its uptake from blood. Huntington disease (HD) associated with reduced synthesis within brain, especially striatum (Shankaran 2017). Previous studies showed that delivery of a low dose Chol (20µg) to R6/2 mice via systemic injection brain-permeable polymeric nanoparticles (NPs-Chol_1.0) improved synaptic and cognitive but not motor defects...
<h3>Background</h3> Cholesterol is a multifaceted molecule essential for brain function (Martin 2014). In the adult brain, cholesterol produced locally by astrocytes and transferred to neurons through apoE-containing lipoproteins (Jurevics & Morell 1995; Mauch 2001). Disruption of pathways has been linked several neurological disorders, including Huntington's disease (HD), genetic, neurodegenerative disorder caused CAG expansion in gene encoding Huntingtin protein (Valenza Cattaneo...