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

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.