Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder.
We previously reported that neuron-specific mutant Polg1 (mitochondrial DNA polymerase) transgenic (Tg) mice exhibited bipolar disorder (BD)-like phenotypes such as periodic activity change and altered circadian rhythm. In this study, we re-evaluated two datasets resulting from DNA microarray analysis to estimate a biological pathway associated with the disorder. The gene lists were derived from the comparison between post-mortem brains of BD patients and control subjects, and from the comparison between the brains of Tg and wild-type mice. Gene ontology analysis showed that 16 categories overlapped in the altered gene expression profiles of BD patients and the mouse model. In the brains of Tg mice, 33 genes showed similar changes in the frontal cortex and hippocampus compared to wild-type mice. Among the 33 genes, SFPQ and PPIF were differentially expressed in post-mortem brains of BD patients compared to control subjects. The only gene consistently down-regulated in both patients and the mouse model was PPIF, which encodes cyclophilin D (CypD), a component of the mitochondrial permeability transition pore. A blood-brain barrier-permeable CypD inhibitor significantly improved the abnormal behaviour of Tg mice at 40 mg/kg.d. These findings collectively suggest that CypD is a promising target for a new drug for BD.
Kubota
Mie
M
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Saitama, Japan.
Kasahara
Takaoki
T
Iwamoto
Kazuya
K
Komori
Atsuko
A
Ishiwata
Mizuho
M
Miyauchi
Taeko
T
Kato
Tadafumi
T
D000818:Animals; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism; D001812:Blood-Brain Barrier; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects
D000081406:Peptidyl-Prolyl Isomerase F; D004272:DNA, Mitochondrial; C000631446:PPIF protein, mouse; D004259:DNA-Directed DNA Polymerase; D021983:Cyclophilins