Systemic manifestation and contribution of peripheral tissues to Huntington’s disease pathogenesis

2021 ◽  
pp. 101358
Author(s):  
Chia-Lung Chuang ◽  
Fabio Demontis
2020 ◽  
Author(s):  
Giulia Birolini ◽  
Marta Valenza ◽  
Ilaria Ottonelli ◽  
Alice Passoni ◽  
Monica Favagrossa ◽  
...  

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.


2019 ◽  
Author(s):  
chiara casella ◽  
Claudia Metzler-Baddeley ◽  
Derek Jones ◽  
Ilona Lipp

Huntington’s disease (HD) is a genetic neurodegenerative disorder, characterised by atrophy of the neostriatum, and cortical grey matter abnormalities. White matter (WM) alterations have recently been identified as a relevant pathophysiological feature of HD, but the etiology of WM degeneration, and its role in disease pathogenesis and progression remain unclear. An increasing body of research suggests that WM changes in HD are due to alterations in myelin-associated biological processes at the cellular and molecular level. This review first discusses evidence from neurochemical studies lending support to the ‘De-myelination hypothesis’ of HD, and pointing towards a role for aberrant myelination and changes in oligodendrocytes in HD WM. Next, evidence from neuroimaging studies is reviewed, the limitations of the described methodologies are discussed and suggested interpretations of findings from published studies are challenged. Although our understanding of HD-associated pathological changes in the brain will increasingly rely on neuroimaging techniques, the shortcomings of these methodologies must not be forgotten. Advances in MRI techniques and tissue modeling will enable a better characterization of the biological properties of WM microstructure, and will allow more specific monitoring of longitudinal changes noninvasively. This, in turn, will provide insight into disease pathogenesis and progression and facilitate the identification of disease-related biomarkers and the specification of outcome measures in clinical trials.


2009 ◽  
Vol 219 (2) ◽  
pp. 385-397 ◽  
Author(s):  
Jenny Sassone ◽  
Clarissa Colciago ◽  
Giuliana Cislaghi ◽  
Vincenzo Silani ◽  
Andrea Ciammola

2012 ◽  
Vol 23 (5-6) ◽  
pp. 367-377 ◽  
Author(s):  
Randi-Michelle Cowin ◽  
Nghiem Bui ◽  
Deanna Graham ◽  
Jennie R. Green ◽  
Lisa A. Yuva-Paylor ◽  
...  

2017 ◽  
Vol 26 (5) ◽  
pp. 751-760 ◽  
Author(s):  
Beata Gruber ◽  
Jolanta Krzysztoń-Russjan ◽  
Irena Bubko ◽  
Jarosław Syska ◽  
Małgorzata Jaworska ◽  
...  

2020 ◽  
Vol 21 (17) ◽  
pp. 6363 ◽  
Author(s):  
Jody Corey-Bloom ◽  
Ryan S. Fischer ◽  
Aeri Kim ◽  
Chase Snell ◽  
Georgia M. Parkin ◽  
...  

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington’s disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30–40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.


2021 ◽  
Author(s):  
Miguel Pellegrini ◽  
Jessica Döring ◽  
Guendalina Bergonzoni ◽  
Federica Perrone ◽  
Giulia Cardamone ◽  
...  

2010 ◽  
Vol 81 (Suppl 1) ◽  
pp. A3.3-A3
Author(s):  
R Vazquez-Manrique ◽  
K Cambon ◽  
N Offner ◽  
A Darbois ◽  
A-M Orfila ◽  
...  

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