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Type 1 cannabinoid receptor (CB1) levels decline in the striatum of animal models of Huntington’s disease (HD) and in the brains of human patients suffering from HD prior to other pathogenic changes. CB1 levels can be elevated by treatment with cannabinoids in non-neuronal cells. We wanted to determine: 1) whether cannabinoid treatment could induce CB1 expression in a striatal cell line, and 2) determine the molecular mechanisms by which cannabinoids and mutant huntingtin regulate CB1 expression. Treatment of striatal cell lines with CB1-specific agonists produced a CB1 receptor-, Akt-, and NF-?B-dependent increase in CB1 promoter activity and mRNA expression that was attenuated in the presence of mutant huntingtin. Cannabinoid treatment was associated with increased expression of the trophic factor BDNF-2 and the mitochondrial regulator PGC1? in the cell types tested. In vivo, cannabinoids may initiate a positive feedback loop increasing receptor expression and restoring cannabinoid-dependent inhibition of neurotransmitter release.

Thesis (M.S.)--University of Alabama at Birmingham, 2008. / Description based on contents viewed Oct. 14, 2008; title from PDF t.p. Includes bibliographical references (p. 53-59).

Huntington's disease (HD) can be regarded as a model neurodegenerative disorder to screen potential genetic based therapeutics and their carriers. It is an autosomal dominant disorder caused by a mutation in a single gene that leads to progressive neurodegeneration caused in part by protein misfolding. The mutation codes for an expanded polyglutamine tract within the Huntingtin gene (HTT) which leads to neuronal loss through a pathological cascade of events. Current treatment strategies include symptom management but no disease-modifying therapies exist. Research has shown that nucleic acid based therapeutics aimed at decreasing HTT expression can prevent, or reverse, the phenotype. Translating such therapies to the clinic is hindered by the blood brain barrier (BBB) and the lack of an easily administrable, non-toxic, immunologically inert delivery vehicle capable of bypassing the BBB. This study examines a range of nucleic acid based therapeutics for their potency and toxicity, and evaluates extracellular vesicles (EVs) as a delivery vehicle through investigation of the biodistribution of brain targeted EVs and an analysis of EV loading. A small interfering RNA (siRNA) targeting a region upstream of the repeat induced potent non-toxic silencing of HTT. In examining EVs as a carrier for therapeutics for neurological diseases including HD, it was found that targeting can increase brain accumulation of EVs but that the physiological characteristics of EVs which make them susceptible to clearance by the reticuloendothelial system (RES) must be further evaluated to bioengineer modified EVs to avoid fast clearance. Lastly, loading by electroporation was found to induce siRNA aggregation which can lead to overestimation of loading by increasing siRNA content in an ultracentrifugation pellet, but cholesterol-conjugated siRNA mixed with EVs was capable of generating silencing in vitro. This thesis examined EV based treatment for HD through the selection of a nucleic acid cargo to silence HTT, and examination of EVs as a delivery vehicle via biodistribution and loading studies. If the loading can be optimised and fast clearance avoided, there is promise in the use of EVs as a carrier of siRNA for HD.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2005. / Bibliography: leaves 370-404.

Polyglutamine expansion disorders are progressive neurodegenerative diseasesthat are caused by the pathological expansion of polyglutamine repeats. Huntington'sdisease (HD) is a polyglutamine disorder caused by the expansion of an existingpolyglutamine tract in a novel protein, Huntingtin (Htt). Oxidative stress has beenimplicated in the neural dysfunction observed in multiple neurodegenerative conditionsincluding HD. The tumor suppressor p53 is a multifunctional protein that has roles inthe cell cycle, apoptosis and neurodevelopment. The role of p53 in HD-associatedneurodegeneration has been studied but not fully elucidated, nor has the role of p53 inoxidative stress toxicity been fully elucidated.Here I present work that demonstrates polyglutamine expansion inducedalterations to p53 stability, localization, and activity. The transcriptional activity of p53was found to have a role in oxidative stress mediated as well as polyglutaminemediated neurotoxicity in vitro. The expression of p53 was also altered in vivo in amouse model of HD as well as in HD brain.Taken together, these data demonstrate a role for p53 in polyglutamine and oxidativestress toxicity.

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