Dysregulated Brain Cholesterol Metabolism Is Linked to Neuroinflammation in Huntington's Disease

• Published in: Movement disorders 2020-07, Vol.35 (7), p.1113-1127
• Main Authors: González‐Guevara, Edith, Cárdenas, Graciela, Pérez‐Severiano, Francisca, Martínez‐Lazcano, Juan Carlos
• Format: Article
• Language: English
• Subjects: ABCA1; Apolipoprotein E; Astrocytes; ATP Binding Cassette Transporter 1 - metabolism; Atrophy; Brain - metabolism; Caudate nucleus; Cell adhesion & migration; Cell migration; Cholesterol; Cholesterol - metabolism; Hereditary diseases; Humans; Huntingtin; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington's disease; Huntingtons disease; Immunosuppressive agents; Inflammation; Lipid Metabolism; Metabolism; Movement disorders; Mutants; Neurodegenerative diseases; Plasma levels; Polyglutamine; Proteins; Receptor density; SREBP; statins; Sterols; Trinucleotide repeat diseases; Trinucleotide repeats
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.28089

ABSTRACT Huntington's disease is an autosomal‐dominant, neurodegenerative disorder caused by a CAG repeat expansion in exon‐1 of the huntingtin gene. Alterations in cholesterol metabolism and distribution have been reported in Huntington's disease, including abnormal interactions between mutant huntingtin and sterol regulatory element‐binding proteins, decreased levels of apolipoprotein E/cholesterol/low‐density lipoprotein receptor complexes, and alterations in the synthesis of ATP‐binding cassette transporter A1. Plasma levels of 24S‐hydroxycholestrol, a key intermediary in cholesterol metabolism and a possible marker in neurodegenerative diseases, decreased proportionally to the degree of caudate nucleus atrophy. The interaction of mutant huntingtin with sterol regulatory element‐binding proteins is of particular interest given that sterol regulatory element‐binding proteins play a dual role: They take part in lipid and cholesterol metabolism, but also in the inflammatory response that induces immune cell migration as well as toxic effects, particularly in astrocytes. This work summarizes current evidence on the metabolic and immune implications of sterol regulatory element‐binding protein dysregulation in Huntington's disease, highlighting the potential use of drugs that modulate these alterations. © 2020 International Parkinson and Movement Disorder Society