Targeting cytochrome P450 46A1 and brain cholesterol 24-hydroxylation to treat neurodegenerative diseases

Abstract

The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by CYP46A1 (cytochrome P450 46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in case neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed.

Keywords: 24-hydroxycholesterol; CYP46A1; acetyl-CoA; brain; cholesterol turnover; mevalonate pathway; sterol flux.

Figure 1.

Schematic representation of the three potential mechanisms (mevalonate pathway, sterol flux, and acetyl-CoA production, colored in green, blue, and violet, respectively) that can integrate a variety of CYP46A1 targeting effects. The initial event, CYP46A1-mediated cholesterol 24-hydroxylation, is colored in magenta. See main text for details. Dashed arrows indicate multiple steps; ↕, the up-down arrow indicates modulation (increase or decrease); PP, pyrophosphate.