TY - JOUR
T1 - Cholestenoic acids regulate motor neuron survival via liver X receptors
AU - Theofilopoulos, Spyridon
AU - Griffiths, William J
AU - Crick, Peter J
AU - Yang, Shanzheng
AU - Meljon, Anna
AU - Ogundare, Michael
AU - Kitambi, Satish Srinivas
AU - Lockhart, Andrew
AU - Tuschl, Karin
AU - Clayton, Peter T
AU - Morris, Andrew A
AU - Martinez, Adelaida
AU - Reddy, M Ashwin
AU - Martinuzzi, Andrea
AU - Bassi, Maria T
AU - Honda, Akira
AU - Mizuochi, Tatsuki
AU - Kimura, Akihiko
AU - Nittono, Hiroshi
AU - De Michele, Giuseppe
AU - Carbone, Rosa
AU - Criscuolo, Chiara
AU - Yau, Joyce L
AU - Seckl, Jonathan R
AU - Schüle, Rebecca
AU - Schöls, Ludger
AU - Sailer, Andreas W
AU - Kuhle, Jens
AU - Fraidakis, Matthew J
AU - Gustafsson, Jan-Åke
AU - Steffensen, Knut R
AU - Björkhem, Ingemar
AU - Ernfors, Patrik
AU - Sjövall, Jan
AU - Arenas, Ernest
AU - Wang, Yuqin
PY - 2014/11
Y1 - 2014/11
N2 - Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3β-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3β,7α-diHCA. Moreover, 3β,7α-diHCA prevented the loss of motor neurons induced by 3β-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.
AB - Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3β-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3β,7α-diHCA. Moreover, 3β,7α-diHCA prevented the loss of motor neurons induced by 3β-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.
KW - Animals
KW - Cell Survival
KW - Cells, Cultured
KW - Cholestenes/blood
KW - Female
KW - Humans
KW - LIM-Homeodomain Proteins/metabolism
KW - Liver X Receptors
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Motor Neurons/physiology
KW - Orphan Nuclear Receptors/metabolism
KW - Paraparesis, Spastic/blood
KW - Transcription Factors/metabolism
KW - Xanthomatosis, Cerebrotendinous/blood
KW - Zebrafish
U2 - 10.1172/JCI68506
DO - 10.1172/JCI68506
M3 - Article
C2 - 25271621
SN - 0021-9738
VL - 124
SP - 4829
EP - 4842
JO - The Journal of Clinical Investigation
JF - The Journal of Clinical Investigation
IS - 11
ER -