Striatal infusion of cholesterol promotes dose-dependent behavioral benefits and exerts disease-modifying effects in Huntington's disease mice
Di Paolo, Eleonora
Bocchi, Vittoria D
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Online Publication Date2020-09-22
Print Publication Date2020-10-07
Permanent link to this recordhttp://hdl.handle.net/10754/665339
MetadataShow full item record
AbstractA variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre-symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini-pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate-controlled manner. All tested doses prevented cognitive decline, while amelioration of disease-related motor defects was dose-dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose-dependent, disease-modifying effect and may be therapeutically relevant in HD.
CitationBirolini, G., Valenza, M., Di Paolo, E., Vezzoli, E., Talpo, F., Maniezzi, C., … Cattaneo, E. (2020). Striatal infusion of cholesterol promotes dose-dependent behavioral benefits and exerts disease-modifying effects in Huntington’s disease mice. EMBO Molecular Medicine. doi:10.15252/emmm.202012519
JournalEMBO Molecular Medicine
Except where otherwise noted, this item's license is described as This is an open access article under theterms of the Creative Commons Attribution 4.0License, which permits use, distribution and reproduc-tion in any medium, provided the original work isproperly cited.
- Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model.
- Authors: Wu J, Ryskamp DA, Liang X, Egorova P, Zakharova O, Hung G, Bezprozvanny I
- Issue date: 2016 Jan 6
- Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington's disease.
- Authors: Birolini G, Valenza M, Ottonelli I, Passoni A, Favagrossa M, Duskey JT, Bombaci M, Vandelli MA, Colombo L, Bagnati R, Caccia C, Leoni V, Taroni F, Forni F, Ruozi B, Salmona M, Tosi G, Cattaneo E
- Issue date: 2021 Feb 10
- Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice.
- Authors: Valenza M, Chen JY, Di Paolo E, Ruozi B, Belletti D, Ferrari Bardile C, Leoni V, Caccia C, Brilli E, Di Donato S, Boido MM, Vercelli A, Vandelli MA, Forni F, Cepeda C, Levine MS, Tosi G, Cattaneo E
- Issue date: 2015 Dec
- Striatal Direct and Indirect Pathway Output Structures Are Differentially Altered in Mouse Models of Huntington's Disease.
- Authors: Barry J, Akopian G, Cepeda C, Levine MS
- Issue date: 2018 May 16
- CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington's disease.
- Authors: Kacher R, Lamazière A, Heck N, Kappes V, Mounier C, Despres G, Dembitskaya Y, Perrin E, Christaller W, Sasidharan Nair S, Messent V, Cartier N, Vanhoutte P, Venance L, Saudou F, Néri C, Caboche J, Betuing S
- Issue date: 2019 Aug 1