Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

Abstract

Background Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable dance-like movements, as well as cognitive deficits and mood changes. A feature of HD is a metabolic disturbance that precedes neurological symptoms. In addition, brain cholesterol synthesis is significantly reduced, which could hamper synaptic transmission. Objective Alterations in lipid metabolism as a potential target for therapeutic intervention in the R6/2 mouse model of HD were examined. Methods Electrophysiological recordings in vitro examined the acute effects of cholesterol-modifying drugs. In addition, behavioral testing, effects on synaptic activity, and measurements of circulating and brain tissue concentrations of cholesterol and the ketone β-hydroxybutyrate (BHB), were examined in symptomatic R6/2 mice and littermate controls raised on normal chow or a ketogenic diet (KD). Results Whole-cell voltage clamp recordings of striatal medium-sized spiny neurons (MSNs) from symptomatic R6/2 mice showed increased frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) compared with littermate controls. Incubation of slices in cholesterol reduced the frequency of large-amplitude sIPSCs. Addition of BHB or the Liver X Receptor (LXR) agonist T0901317 reduced the frequency and amplitude of sIPSCs. Surprisingly, incubation in simvastatin to reduce cholesterol levels also decreased the frequency of sIPSCs. HD mice fed the KD lost weight more gradually, performed better in an open field, had fewer stereotypies and lower brain levels of cholesterol than mice fed a regular diet. Conclusions Lipid metabolism represents a potential target for therapeutic intervention in HD. Modifying cholesterol or ketone levels acutely in the brain can partially rescue synaptic alterations, and the KD can prevent weight loss and improve some behavioral abnormalities.

HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression

“…Virtually all eukaryotic cells including astrocytes produce exosomes, which serve as a major extracellular vehicle to transport miRNA and proteins among cells [ 13 , 72 ]. Thus, we first determined whether Tat-induced miR-132 expression would lead to increased miR-132 in astrocyte-derived exosomes.…”

“…MicroRNA (miRNA) are master translation regulators which generally initiate degradation of messenger RNA (mRNA) and translational repression [ 12 ]; they are often dysregulated in diseases [ 13 – 15 ]. Viral infections in particular have been shown to disrupt cellular miRNA profiles and thus modulate viral replication or the transcriptional machinery of the host [ 16 ].…”

HttQ111/+ Huntington’s Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction

“…Of interest in this context is the observation that a high fat diet in mice induced changes in the expression of Mlh1 , a genetic modifier of both CAG instability and the HD pathogenic process [ 40, 55 ]. Further, a ketogenic diet (16/0/84% kcal from protein/carbohydrate/fat) ameliorated some phenotypes in R6/2 HD transgenic mice [ 56 ]. Overall, the results of our histopathological and brain structural analyses performed in both the high fat diet-treated mice and in aged mice highlight a subtle and slowly progressing pathogenic process driven by a single Htt Q 111 allele that is neither strongly manifest by 18 months of age, nor strongly modified by a diet as a metabolic stressor.…”

Statins and the Brain: More than Lipid Lowering Agents?

“…The possibility that changes in brain cholesterol homeostasis occur in HD has been suggested over the past several years [222]. Indeed, in HD patients and mouse models of HD, growing evidence has demonstrated early and long-lasting alterations in the cholesterol biosynthesis [223].…”