Article

Overexpression of the α(1B)-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy

Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Nature Medicine (Impact Factor: 28.05). 01/2001; 6(12):1388-94. DOI: 10.1038/82207
Source: PubMed

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.

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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. "
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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). "
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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). "
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