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Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons.

ABSTRACT: Rett syndrome is a neurodevelopmental disorder caused by Mecp2 gene mutations. In RTT patients and Mecp2-null (Mecp2(-/Y)) mice, norepinephrine (NE) content drops significantly, which may play a role in breathing arrhythmia, sleep disorders and sudden death. However, the underlying mechanisms for the NE defect are not fully understood. The NE defect may result from decreased NE biosynthesis, loss of catecholaminergic neurons or both. Although deficiency in tyrosine hydroxylase (TH) has been demonstrated, it is possible that dopamine beta-hydroxylase (DBH), the critical enzyme converting dopamine to NE, is also affected. To test these possibilities, we studied DBH expressions in pontine catecholaminergic neurons of Mecp2(-/Y) mice identified with breathing abnormalities. In comparison to the wild type, Mecp2(-/Y) mice at 2months of age showed approximately 50% decrease in the expressions of DBH and TH, at both protein and mRNA levels in the locus coeruleus (LC) region. Consistently, DBH and TH immunoreactivity was markedly decreased in LC neurons of Mecp2(-/Y) mice. No evidence was found for selective deficiency in TH- or DBH-containing neurons in Mecp2(-/Y) mice, as almost all TH-positive cells expressed DBH. By counting TH-immunoreactive cells in the LC, we found that the Mecp2(-/Y) mice lost only approximately 5% of the catecholaminergic neurons as compared to wild-type, although their LC volume shrank by approximately 15%. These results strongly suggest that the NE defect in Mecp2(-/Y) mice is likely to result from deficient expression of not only TH but also DBH without significant loss of catecholaminergic neurons in the LC.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4132834 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons.

Zhang Xiaoli X Su Junda J Rojas Asheebo A Jiang Chun C

Biochemical and biophysical research communications 20100301 2

Rett syndrome is a neurodevelopmental disorder caused by Mecp2 gene mutations. In RTT patients and Mecp2-null (Mecp2(-/Y)) mice, norepinephrine (NE) content drops significantly, which may play a role in breathing arrhythmia, sleep disorders and sudden death. However, the underlying mechanisms for the NE defect are not fully understood. The NE defect may result from decreased NE biosynthesis, loss of catecholaminergic neurons or both. Although deficiency in tyrosine hydroxylase (TH) has been demo ...[more]

PMID: 20193660

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Project description:In the sympatho-adrenal system, angiotensin II (Ang II) acts as a key neuromodulatory component. At sympathetic nerve terminals, Ang II influences sympathetic transmission by enhancing norepinephrine (NE) synthesis, facilitating NE release and inhibiting NE uptake. Previously, it was demonstrated that tyrosine hydroxylase (TH) mRNA is trafficked to the distal axons of primary superior cervical ganglia (SCG) neurons, directed by a cis-acting regulatory element (i.e. zipcode) located in the 3'UTR of the transcript. Results of metabolic labeling studies established that the mRNA is locally translated. It was further shown that the axonal trafficking of the mRNA encoding the enzyme plays an important role in mediating dopamine (DA) and NE synthesis and may facilitate the maintenance of axonal catecholamine levels. In the present study, the hypothesis was tested that Ang II induces NE synthesis in rat primary SCG neurons via the modulation of the trafficking of the mRNAs encoding the catecholamine synthesizing enzymes TH and dopamine β-hydroxylase (DBH). Treatment of SCG neurons with the Ang II receptor type 1 (AT1R) agonist, L-162,313, increases the axonal levels of TH and DBH mRNA and protein and results in elevated NE levels. Conversely, treatment of rat SCG neurons with the AT1R antagonist, Eprosartan, abolished the L-162,313-mediated increase in axonal levels of TH and DBH mRNA and protein. In a first attempt to identify the proteins involved in the Ang II-mediated axonal transport of TH mRNA, we used a biotinylated 50-nucleotide TH RNA zipcode as bait in the affinity purification of TH zipcode-associated proteins. Mass spectrometric analysis of the TH zipcode ribonucleoprotein (RNP) complex immune-purified from SCG neurons led to the identification of 163 somal and 127 axonal proteins functionally involved in binding nucleic acids, the translational machinery or acting as subunits of cytoskeletal and motor proteins. Surprisingly, immune-purification of the TH axonal trafficking complex, results in the acquisition of DBH mRNA, suggesting that these mRNAs maybe transported to the axon together, possibly in the same RNP complex. Taken together, our results point to a novel mechanism by which Ang II participates in the regulation of axonal synthesis of NE by modulating the local trafficking and expression of TH and DBH, two key enzymes involved in the catecholamine biosynthetic pathway.

Project description:Recessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7) is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively), to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount in situ mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic tyrosine hydroxylase-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the dopamine transporter-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia), which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic neuronal loss and dopamine-dependent bradykinesia), representing therefore a valid tool for investigating the mechanisms of selective dopaminergic neuronal death, and screening for modifier genes and therapeutic compounds.

Project description:Several neurodegenerative diseases involve loss of catecholamine neurons--Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"--inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of (18)F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of (18)F-dopamine-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen (18)F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial (18)F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons.

Dataset Information

Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons.

Publications

Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons.

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