Overexpression of the α1B-adrenergic receptor causes apoptotic neurodegeneration: Multiple system at

Abstract

Progress toward elucidating the function of α1B-adrenergic receptors (α1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate α1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active α1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in α1B-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 α1AR antagonist terazosin, indicating that α1AR signaling participated directly in the pathology. Our results indicate that overstimulation of α1BAR 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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Zuscik, M., Sands, S., Ross, S. et al. Overexpression of the α_1B-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy. Nat Med 6, 1388–1394 (2000). https://doi.org/10.1038/82207

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