Journal
NEUROBIOLOGY OF AGING
Volume 31, Issue 1, Pages 88-98Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2008.03.004
Keywords
Familial British Dementia; Familial Danish Dementia; Alzheimer's disease; Neurodegeneration; Homodimerization
Categories
Funding
- Empeirikion Foundation
- University of Athens
- NIH [AG010491, NS051715]
- Alzheimer's Association
- American Heart Association
- Greek State Scholarships Foundation
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS051715] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG010491] Funding Source: NIH RePORTER
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Familial British and Familial Danish Dementia (FBD and FDD) are two dominantly inherited neurodegenerative diseases that present striking similarities with Alzheimer's disease. The genetic defects underlying those dementias are mutations in the gene that encodes for BRI2 protein. Cleavage of mutated BRI2 by furin releases the peptides ABri or ADan, which accumulate in the brains of patients. BRI2 normal function is yet unknown. To unwind aspects of its cellular role, we investigated the possibility that BRI2 forms dimers, based on structural elements of the protein, the GXXXG motif within its transmembrane domain and the odd number of cysteine residues. We found that BRI2 dimerizes in cells and that dimers are held via non-covalent interactions and via disulfide bridges between the cysteines at position 89. Additionally, we showed that BRI2 dimers are formed in the ER and appear at the cell surface. Finally, BRI2 dimers were found to exist in mouse brain. Revealing the physiological properties of BRI2 is critical in the elucidation of the deviations that lead to neurodegeneration. (C) 2008 Elsevier Inc. All rights reserved.
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