Assembly of a perivascular astrocyte protein scaffold at the mammalian blood-brain barrier is dependent on alpha-syntrophin.
alpha-Syntrophin, a member of the dystrophin-associated protein complex, is required for proper localization of the water channel aquaporin-4 at the blood-brain barrier. Mice lacking alpha-syntrophin have reduced levels of aquaporin-4 in perivascular astroglial endfeet. Consequently, they exhibit reduced edema and infarct volume in brain trauma models and reduced K+ clearance from the neuropil, leading to increased seizure susceptibility. We have used the alpha-syntrophin null mice to investigate whether alpha-syntrophin is required for proper localization of other components of the dystrophin complex at the blood-brain barrier. We find that alpha-syntrophin is required for the full recruitment of gamma2-syntrophin and alpha-dystrobrevin-2 to glial endfeet in adult cerebellum. In contrast, the localization of beta1- and beta2-syntrophin and alpha-dystrobrevin-1 at the blood-brain barrier is not dependent on the presence of alpha-syntrophin. The localization patterns of alpha-dystrobrevin-1 and -2 in wild type cerebellum are strikingly different; while alpha-dystrobrevin-1 is present in glial endfeet throughout the cerebellum, alpha-dystrobrevin-2 is restricted to glial endfeet in the granular layer alone. Finally, we show that the enrichment of dystrophin in glial endfeet depends on the presence of alpha-syntrophin. This finding is the first demonstration that dystrophin localization is dependent on syntrophin. Since the localization of gamma2-syntrophin, alpha-dystrobrevin-2, and dystrophin is contingent on alpha-syntrophin, we conclude that alpha-syntrophin is a central organizer of the astrocyte dystrophin complex, an important molecular scaffold for localization of aquaporin-4 at the blood-brain barrier.
Bragg
April D
AD
Department of Physiology and Biophysics, Health Sciences Building, Rm G424, 1959 NE Pacific St, University of Washington, Seattle, 98195, USA. abragg@u.washington.edu
Amiry-Moghaddam
Mahmood
M
Ottersen
Ole P
OP
Adams
Marvin E
ME
Froehner
Stanley C
SC
D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002531:Cerebellum / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D049029:Dystrophin-Associated Proteins / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000502:physiology; D014882:Water-Electrolyte Balance / Q000235:genetics
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009124:Muscle Proteins; C098885:dystrobrevin; C091824:syntrophin; C091825:syntrophin alpha1