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

Citation
Mj. Zuscik et al., Overexpression of the alpha(1B)-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy, NAT MED, 6(12), 2000, pp. 1388-1394
Citations number
30
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
Journal title
NATURE MEDICINE
ISSN journal
10788956 → ACNP
Volume
6
Issue
12
Year of publication
2000
Pages
1388 - 1394
Database
ISI
SICI code
1078-8956(200012)6:12<1388:OOTARC>2.0.ZU;2-S
Abstract
Progress toward elucidating the function of alpha (1B)-adrenergic receptors (alpha (1B)ARs) in the central nervous system has been constrained by a la ck of agonists and antagonists with adequate alpha (1B)-specificity. We hav e obviated this constraint by generating transgenic mice engineered to over express either wild-type or constitutively active alpha (1B)ARs in tissues that normally express the receptor, including the brain. All transgenic lin es showed granulovacular neurodegeneration, beginning in alpha (1B)-express ing domains of the brain and progressing with age to encompass all areas. T he degeneration was apoptotic and did not occur in non-transgenic mice. Cor respondingly, transgenic mice showed an age-progressive hindlimb disorder t hat was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degenera tion 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 s eizure) could be partially rescued with the alpha (1)AR antagonist terazosi n, indicating that alpha (1)AR signaling participated directly in the patho logy. Our results indicate that overstimulation of alpha (1B)AR leads to ap optotic neurodegeneration with a corresponding multiple system atrophy indi cative of Shy-Drager syndrome, a disease whose etiology is unknown.