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Centonze D, Rossi S, Napoli I, Mercaldo V, Lacoux C, Ferrari F, Ciotti MT, De Chiara V, Prosperetti C, Maccarrone M, Fezza F, Calabresi P, Bernardi G, Bagni C. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. J Neurosci. 2007 Aug 15;27(33):8885-92. PubMed.
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The Brain Cytoplasmic RNA BC1 Regulates Dopamine D2 Receptor Mediated Transmission in the Striatum
The work performed by Centonze et al. (Centonze et al., 2007) identifies BC1 RNA as a regulator of dopamine (DA) transmission in the striatum. Interestingly, the fact that BC1 can modulate D2 receptors strongly implies that deregulation of the expression levels of BC1 RNA could alter DA transmission.
It is known that motor activity and cognition are regulated to a certain extent by ordered DA transmission, and that several neurological and psychiatric conditions are due to alterations in DA D2 receptor signaling. For instance, in Parkinson disease, the second most common neurological disorder, reduced sensitivity of the D2 receptor has been reported, and one could hypothesize that downregulation of BC1 RNA could improve this condition by enhancing the functional response of the D2 receptor. It would, for instance, be interesting to see whether the reduced sensitivity of striatal D2DR in the DJ-1 knockout mouse model for familial Parkinson disease as described by Goldberg et al. (Goldberg et al., 2003) would be ameliorated if these mice were to be crossed to the BC1 KO mice.
Additionally, one could also consider that the overexpression of BC1 RNA could lead to downregulation of the functional response of the D2 receptor, and this approach could be used to improve psychiatric conditions, such as schizophrenia.
In conclusion, the identification of BC1 RNA as a regulator of the functional response of the D2 receptor could open up new avenues in pursuit of identifying novel therapeutic targets for these neurological disorders.
References:
Centonze D, Rossi S, Napoli I, Mercaldo V, Lacoux C, Ferrari F, Ciotti MT, De Chiara V, Prosperetti C, Maccarrone M, Fezza F, Calabresi P, Bernardi G, Bagni C. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. J Neurosci. 2007 Aug 15;27(33):8885-92. PubMed.
Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron. 2005 Feb 17;45(4):489-96. PubMed.
View all comments by Vanessa MoraisThe thrust of this paper is that the noncoding RNA BC1 is responsible for regulating D2-mediated synaptic transmission. Perhaps the greatest strength of the study is the robust neurophysiology and pharmacology with tight controls. That data set shows, using corticostriatal slice preparations, that the dopaminergic perturbation (hypersensitivity) is specific for the D2 receptor in BC1-knockout mice. This is especially important in light of the “anxiety” phenotype these mice express, and the probable role(s) of striatal dopamine in human psychiatric diseases. The authors then show that BC1 is apparently present in axons and in striatal GABAergic cells.
A challenge for this work is that the actual mechanism by which BC1 works is as yet poorly understood. That BC1 may be present in axons has been shown previously; however, the significance of axonal BC1 remains obscure. The authors show that D2DR mRNA and protein levels are not dramatically decreased (protein appears increased) in the BC1 KO mice, and thus conclude that “D2DR-mediated transmission in this brain area is under the control of BC1 RNA, through a process likely to be mediated by a negative influence on D2DR insertion, turnover, and/or stability.”
The subject matter is complex. It relates to the diverse fields of noncoding RNA, synaptic regulation, dopamine pharmacology and physiology, transgenic mice, cell biology, and translational regulation in neurons. Few investigators are expert in all of these fields, and I tip my cap to these authors for undertaking the challenge. In a general sense, they have added another piece to the amazing puzzle of noncoding RNA biology. More specifically, they demonstrate expertise and a possibly ideal model to tease out the complex mechanism of the brain-enriched noncoding RNA termed BC1.
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