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

Nature Medicine volume 6, pages 1388–1394 (2000)Cite this article

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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Figure 1: General characterization of transgenic mice.
Figure 2: Locomotor dysfunction phenotype in transgenic mice.
Figure 3: Seizure phenotype in transgenic mice.
Figure 4: Neurodegeneration at 10 months.
Figure 5: Neurodegeneration at 18–21 months of age.

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Acknowledgements

The authors thank the Cleveland Clinic Foundation Transgenic Core for doing the transgene injections that produced founder mice. Histology and immunohistochemistry were done by G. Vince and M. Garcia of the Department of Biomedical Engineering at the Cleveland Clinic Foundation Lerner Research Institute. DNA was sequenced by the Cleveland Clinic Sequencing Core. This work was funded by RO1HL61438 (D.M.P.), F32HL1000402 (M.J.Z.), an American Heart Established Investigator Award (D.M.P.) and an unrestricted research grant from Glaxo Wellcome (D.M.P.).

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  1. Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, 44195, Ohio, USA

    Michael J. Zuscik, Sean A. Ross, David J. J. Waugh, Robert J. Gaivin & Dianne M. Perez

  2. Department of Pharmacology, The University of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, 78284, Texas, USA

    Scott Sands & David Morilak

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  1. Michael J. Zuscik
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Correspondence to Dianne M. Perez.

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Zuscik, M., Sands, S., Ross, S. et al. Overexpression of the α1B-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy. Nat Med 6, 1388–1394 (2000). https://doi.org/10.1038/82207

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