Alpha-B-crystallin, a major element of the vertebrate lens, is also expressed in extralenticular tissues. Recent findings indicate that alpha- B-crystallin should be considered a """"""""heat shock"""""""" or """"""""stress"""""""" protein. First, the alpha-crystallins share homologous sequences with the family of low MW heat shock proteins (hsps). Second, although alpha-B-crystallin is constitutively expressed in some tissues, it can be upregulated dramatically by a variety of classical """"""""stress agents, including heat shock, oxidative stress, and transitional metals. A singular example of alpha-B-crystallin expression occurs in the childhood leukodystrophy, Alexander disease, in which astrocytes accumulate large, proteinaceous inclusions known as Rosenthal fibers. The major components of these inclusions are alpha-B-crystallin and the related small MW heat shock protein, hsp27. Over the first two years of this grant we have found that a). levels of mRNA and protein for alpha-B-crystallin and hsp 27 are markedly elevated in Alexander disease CNS, b). astrocytes upregulate these two genes both coordinately and independently in response to a variety of """"""""stress"""""""" agents, and c). alpha-B-crystallin protects astroglial cells from the stress of increased salt concentration. We propose to continue our studies on Alexander disease and to focus on the regulation of small MW heat shock proteins in the central nervous system and shall follow several lines of inquiry: I. Are other hsps overexpressed In Alexander disease and if so, are they involved in RP formation? II. Does the stress-induced increase in alpha-B-crystallin and hsp27 in astrocytes occur at a transcriptional level? III. Can we identify proteins that act as transcriptional regulators for alpha-B-crystallin and hsp27? Do these proteins function in stress responses? Are these proteins expressed in Alexander disease and might they play a role in the accumulation of stress proteins in the Alexander CNS? IV. Does alpha-B-crystallin protect cells from specific """"""""stresses"""""""" or does it have general protective properties against many """"""""stresses""""""""?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY009331-04
Application #
2162932
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1991-05-01
Project End
1997-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Hsiao, Victoria C; Tian, Rujin; Long, Heather et al. (2005) Alexander-disease mutation of GFAP causes filament disorganization and decreased solubility of GFAP. J Cell Sci 118:2057-65
Li, Rong; Messing, Albee; Goldman, James E et al. (2002) GFAP mutations in Alexander disease. Int J Dev Neurosci 20:259-68
Brenner, M; Johnson, A B; Boespflug-Tanguy, O et al. (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27:117-20
Head, M W; Hurwitz, L; Kegel, K et al. (2000) AlphaB-crystallin regulates intermediate filament organization in situ. Neuroreport 11:361-5
Head, M W; Goldman, J E (2000) Small heat shock proteins, the cytoskeleton, and inclusion body formation. Neuropathol Appl Neurobiol 26:304-12
Koyama, Y; Goldman, J E (1999) Formation of GFAP cytoplasmic inclusions in astrocytes and their disaggregation by alphaB-crystallin. Am J Pathol 154:1563-72
Wisniewski, T; Goldman, J E (1998) Alpha B-crystallin is associated with intermediate filaments in astrocytoma cells. Neurochem Res 23:385-92
Messing, A; Head, M W; Galles, K et al. (1998) Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol 152:391-8
Head, M W; Hurwitz, L; Goldman, J E (1996) Transcription regulation of alpha B-crystallin in astrocytes: analysis of HSF and AP1 activation by different types of physiological stress. J Cell Sci 109 ( Pt 5):1029-39
Chin, S S; Goldman, J E (1996) Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol 55:499-508

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