Overexpression of the α(1B)-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy
ABSTRACT Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.
- SourceAvailable from: Mohamed Jaber
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- "The fortuitous discovery that transgenic mice over-expressing the 1B-adrenergic receptor bear several features with MSA, speared curiosity among researchers, as implication of the NE transmission in the pathogenesis of MSA was never previously suspected (Zuscik et al. 2000). Although the group that has developed these mice do acknowledge that MSA is not due to a mutated form of this receptor, this transgenic model may nevertheless be useful in dissecting the neurotransmission pathway that might be implicated in this disease. "
ABSTRACT: The use of animals as models of neurodegenerative disorders has allowed the determination of biological targets and biomarkers of several diseases, has yielded new therapeutical perspectives, and is essential before performing novel clinical assays. This review discusses the nature, use, and limits of animal models and how to obtain them for several neurodegenerative disorders such as multiple system atrophy, amyotrophic lateral sclerosis, and Huntington’s disease, with a special emphasis on Parkinson’s and Alzheimer’s diseases. When possible, rodent, invertebrate and primate models are presented and discussed in relation to human disease. Finally, we highlight discrepancies between animal models and human neuropathology leading to question the pertinence of some of these findings to human disorders probably because of the wide spectrum of parameters defining a disease. Another point raised by these studies is the growing necessity to standardize the experimental procedures used to obtain an animal model, housing and breeding conditions, assessments of phenotypes investigated and, ultimately the interpretation of results obtained and their relevance to the pathology. KeywordsParkinson’s disease-Huntington disease-Alzheimer’s disease-Amyotrophic lateral sclerosis-Multiple system atrophy-Tauopathies-Nucleotide repeats01/2010: pages 49-101;
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- "Tissuespecific distribution of the CAM α 1A -and CAM α 1B -ARs was confirmed by saturation binding assays with the α 1 -AR selective radioligand 2-[β-(4hydroxy-3-[ 125 -I]iodophenyl) ethylaminomethyl]tetralone ([ 125 I]-HEAT) (Rorabaugh et al., 2005a; Zuscik et al., 2000). Constitutive activity of these receptors in the mouse brain and other tissues was determined by measuring basal levels of inositol 1,4,5-trisphosphate production (Rorabaugh et al., 2005a; Zuscik et al., 2000). "
ABSTRACT: Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive-compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of alpha(1)-adrenergic receptors (alpha(1)-ARs). Yet, it is unclear whether increased alpha(1)-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant alpha(1A)-ARs (CAM alpha(1A)-AR) or CAM alpha(1B)-ARs were used to examine the effects of alpha(1A)- and alpha(1B)-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM alpha(1A)-AR mice, but not CAM alpha(1B)-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective alpha(1)-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an alpha(1A)-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM alpha(1A)-AR mice but not in CAM alpha(1B)-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM alpha(1A)-AR, and CAM alpha(1B)-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that alpha(1A)- and alpha(1B)-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that alpha(1A)-ARs may be a useful therapeutic target for the treatment of depression.Brain research 07/2009; 1285:148-57. DOI:10.1016/j.brainres.2009.06.035 · 2.83 Impact Factor
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- "In recent years, the genetic modeling of a mouse strain that overexpresses a1b-ARs led to spontaneous seizures and widespread degeneration (Zuscik et al., 2000). Overactivity of a1b-ARs is supposed to trigger neuronal death, which depends upon allosteric interaction between a1b-AR and N-methyl-d-aspartate (NMDA)–glutamate receptors, according to Paladini et al. (2001). "
ABSTRACT: The role of alpha 1b-adrenergic receptor (alpha 1b-AR) in relation with neuronal degeneration, drug addiction, and seizure susceptibility has recently emerged. In particular, mice that overexpress alpha 1b-AR undergo spontaneous epileptic seizures and progressive neuronal loss in a variety of brain areas. Therefore, one should expect that the blockade of alpha 1b-AR leads to anticonvulsant and neuroprotective effects. However, the lack of alpha 1b-AR antagonists does not allow testing of this hypothesis. The development of alpha 1b-AR knockout (KO) mice led us to measure seizure susceptibility and neurodegeneration following systemic excitotoxins in these mice. We found that alpha 1b-AR KO mice are markedly resistant to kainate- and pilocarpine-induced seizures. Moreover, when marked seizure duration and severity are obtained by doubling the dose of chemoconvulsants in alpha 1b-AR KO, neuronal degeneration never occurs. These data indicate that alpha 1b-AR per se plays a fundamental role in the mechanisms responsible for seizure onset, severity, and duration, whereas the brain damage observed in alpha 1b-AR-overexpressing mice is likely to be a secondary phenomenon. In fact, the absence of alpha 1b-AR confers resistance to neurotoxicity induced by seizures/chemoconvulsants. These data, although confirming a pivotal role of alpha 1b-AR in modulating seizure threshold and neuronal death, offer a novel target, which may be used to develop novel anticonvulsants and neuroprotective agents.Epilepsia 02/2009; 50 Suppl 1:59-64. DOI:10.1111/j.1528-1167.2008.01972.x · 4.58 Impact Factor