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

Michael J. Zuscik, Scott Sands, Sean A. Ross, David J.J. Waugh, Robert J. Gaivin, David Morilak, Dianne M. Perez

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


Progress toward elucidating the function of α(1B)-adrenergic receptors (α(1B)ARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate α(1B)-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active α(1B)ARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in α(1B)-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 α(1B)AR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.

Original languageEnglish (US)
Pages (from-to)1388-1394
Number of pages7
JournalNature Medicine
Issue number12
StatePublished - 2000

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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