Rines E3 ubiquitin ligase regulates MAO-A levels and emotional responses.
Monoamine oxidase A (MAO-A), the catabolic enzyme of norepinephrine and serotonin, plays a critical role in emotional and social behavior. However, the control and impact of endogenous MAO-A levels in the brain remains unknown. Here we show that the RING finger-type E3 ubiquitin ligase Rines/RNF180 regulates brain MAO-A subset, monoamine levels, and emotional behavior. Rines interacted with MAO-A and promoted its ubiquitination and degradation. Rines knock-out mice displayed impaired stress responses, enhanced anxiety, and affiliative behavior. Norepinephrine and serotonin levels were altered in the locus ceruleus, prefrontal cortex, and amygdala in either stressed or resting conditions, and MAO-A enzymatic activity was enhanced in the locus ceruleus in Rines knock-out mice. Treatment of Rines knock-out mice with MAO inhibitors showed genotype-specific effects on some of the abnormal affective behaviors. These results indicated that the control of emotional behavior by Rines is partly due to the regulation of MAO-A levels. These findings verify that Rines is a critical regulator of the monoaminergic system and emotional behavior and identify a promising candidate drug target for treating diseases associated with emotion.
Laboratory for Behavioral and Developmental Disorders, Molecular Neuropathology Group, and Support Unit for Animal Resources Development, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
Miyuki
M
Kabayama
Kazuto
K
Sakoori
Kazuyuki
K
Yamada
Veravej G
VG
Ornthanalai
Maya
M
Ota
Naoko
N
Morimura
Kei-ichi
K
Katayama
Niall P
NP
Murphy
Jun
J
Aruga
D000161:Acoustic Stimulation; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001921:Brain / Q000201:enzymology* / Q000648:ultrastructure; D003623:Dark Adaptation / Q000235:genetics; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007398:Interpersonal Relations; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D011930:Reaction Time / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics; D013550:Swimming / Q000502:physiology; D014191:Tranylcypromine / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; D008995:Monoamine Oxidase; D044767:Ubiquitin-Protein Ligases