title: 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.
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Conny
authors.initials: C
authors.lastname: Tran
authors.affiliation: Pasarow Mass Spectrometry Laboratory, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Hwang
authors.affiliation: Department of Chemistry and Biochemistry, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Chemistry and Biochemistry, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.affiliation: Pasarow Mass Spectrometry Laboratory, David Geffen School of Medicine, University of California Los Angeles, CA, USA.|Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, CA, USA.|Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology*; D055423:Diet, Ketogenic; D005260:Female; D006816:Huntington Disease / Q000178:diet therapy / Q000378:metabolism* / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D019821:Simvastatin / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects
chemical_list: D002784:Cholesterol; D019821:Simvastatin; D020155:3-Hydroxybutyric Acid
keywords: R6/2 model; cholesterol; electrophysiology; ketogenic diet; synaptic activity