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H03 Cerebral and extracerebral cholesterol biosynthesis is impaired in Huntington's disease patients
  1. V Leoni1,
  2. C Mariotti1,
  3. L Nanetti1,
  4. C Tomasello1,
  5. E Salvatore2,
  6. G De Michele2,
  7. F Soletti3,
  8. A Bentivoglio3,
  9. M Bandettini di Poggio4,
  10. G Abbruzzese4,
  11. S Piacentini5,
  12. F Squitieri6,
  13. M Valenza7,
  14. E Cattaneo7,
  15. S Di Donato1
  1. 1Unit of Genetic of Neurodegenerative and Metabolic Diseases, IRCCS National Institute of Neurology, Milano, Italy
  2. 2Department of Neurological Science, University of Napoli, Napoli, Italy
  3. 3Università Cattolica del Sacro Cuore, Istituto di Neurologia, Roma, Italy
  4. 4Department of Neuroscience Ophtalmology and Genetics, Genova, Italy
  5. 5Department of Neurology, University of Florence, Firenze, Italy
  6. 6Neuropharmacology Unit, IRCCS Neuromed, Pozzilli (IS), Italy
  7. 7Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milano, Milano, Italy


Background Cholesterol in the CNS is fundamental for membrane trafficking, signal transduction and synaptogenesis and almost all the brain cholesterol is synthetised locally. Homeostasis is maintained through a neuronal specific cholesterol 24-hydroxylase which converts cholesterol into 24-hydroxycholesterol (24OHC). The levels of 24OHC in blood thus reflect the number of active neurons and the volume of the grey matter. We previously found that plasma levels of 24OHC were progressively reduced in early Huntington's disease (HD)1 and that cholesterol biosynthesis was significantly impaired in the brain of multiple mouse HD models, and in fibroblasts of HD patients.2

Methods We analysed by mass spectrometry plasma levels of the cholesterol precursor lathosterol and lanosterol (marker of cholesterol biosynthesis), 24OHC and bile acid precursor 27-hydroxycholesterol, in 130 HD gene positive subjects (from presymptomatic to advanced stage of disease).

Results We found that plasma levels of lathosterol and lanosterol, together with 24OHC and 27OHC, were reduced in all HD patients compared with healthy controls (p<0.001).

Conclusion Whole body cholesterol synthesis and brain derived 24OHC were significantly decreased following the disease burden. We suggest that the significant decrease in plasma 24OHC levels we reported in early HD1 are associated with two concurrent mechanisms, that is, the progressive loss in grey matter linked to the neurodegenerative process and the impairment in brain cholesterol biosynthesis, in agreement with our previous findings across multiple rodent models of HD2.

  • oxysterol
  • cholesterol
  • neurodegeneration

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