CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington’s disease.

CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington’s disease.

Publication date: Jul 09, 2019

Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington’s disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin’s gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington’s disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington’s disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington’s disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington’s disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington’s disease.

Kacher, R., Lamazi`ere, A., Heck, N., , Kappes, Mounier, C., Despres, G., Dembitskaya, Y., Perrin, E., Christaller, W., Sasidharan Nair, S., , Messent, Cartier, N., Vanhoutte, P., Venance, L., Saudou, F., N’eri, C., Caboche, J., and Betuing, S. CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington’s disease. 06566. 2019 Brain.

Concepts Keywords
Autophagy Autophagy
Autosomal Dominant Cholesterol
Axonal Transport Neurodegeneration
BDNF Huntington’s disease
Brain Neuroprotection
Cholesterol Neurology
Endosome Huntingtin
Enzyme Sterols
Gene Organ systems
Homeostasis Neuroscience
Huntingtin Branches of biology
Huntington Brain disorders
Hydrolase Innovative disease
Hydroxylation
Metabolism
Mice
Mutant
Mutation
Neurodegenerative
Neurodegenerative Diseases
Neurodegenerative Disorders
Neuroprotection
Neuroprotective
Pathogenesis
Proteasome
Striatal
Synaptic
Transcriptomic
TrkB
Vesicle

Semantics

Type Source Name
pathway BSID Neurodegenerative Diseases
gene UNIPROT LARGE1
gene UNIPROT NTRK2
gene UNIPROT BDNF
pathway BSID Proteasome
disease MESH multiple
disease DOID neurodegenerative disease
disease MESH neurodegenerative disorders
drug DRUGBANK Cholesterol
disease MESH brain disorders
pathway BSID Cholesterol metabolism
gene UNIPROT CYP46A1

Original Article

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