Molecular
Studies of Astrocyte Function
Our
laboratory studies the molecular biology of astrocytes, the most common
cell type in the central nervous system (CNS). Astrocytes are responsible
for many of the homeostatic controls in the CNS, such as maintaining the
blood-brain barrier and proper neurotransmitter levels.
Astrocyte serve as precursors for neurons and oligodendrocytes
during development, and also serve as stem cells for the production of
these cell types in the adult. CNS
injury stimulates astrocytes to undergo a reactive response, which
contributes to healing but can also lead to further damage.
Our work focuses on the transcriptional regulation of a gene
encoding an intermediate filament protein specific to astrocytes, glial
fibrillary acidic protein (GFAP), and on the biological role of this
protein. The GFAP gene is of interest because it is turned on as
astrocytes mature, and its activity increases dramatically during the
reactive response. Thus, study of GFAP transcription will yield insights
into mechanisms governing development, reaction to injury, and cell
specificity, ultimately allowing these processes to be manipulated.
In
our transcriptional studies we have identified a 2.2kb GFAP promoter
segment that retains a high degree of astrocyte specificity and also
responds to injury by increased activity.
Current studies focus on identifying precise sequences that control
these properties, and then discovering the regulatory pathways that
operate through those sequences. In
studies of GFAP function, we have found that absence of the protein
renders mice hypersensitive to traumatic spinal cord injury, revealing a
novel role for GFAP in structural support. We have also discovered that
mutations within the coding sequence of the GFAP gene are responsible for
many cases of Alexander disease, a rare but often fatal neurodegenerative
disorder of humans. The
pathological hallmark of Alexander disease is the accumulation of protein
aggregates in astrocytes. Interestingly,
although the primary defect is in astrocytes, oligodendrocyte and neuronal
functions are severely disrupted in this disease.
We are working on the mechanism by which the GFAP mutations produce
these effects. These results
will be of interest not only for Alexander disease, but also for other
protein aggregate disorders like Parkinson’s disease, ALS and
Alzheimer’s disease.
Michael
Brenner received his Ph.D. in Biochemistry from the University of
California, Berkeley. He served on the faculty of
Harvard
College
and
Temple
University
Medical
School
,
and was a Research Scientist at the National Institutes of Health before
joining UAB in 1998. He is presently Associate Professor of Neurobiology
with a joint appointment in the Department of Physical Medicine &
Rehabilitation.
For a more detailed description of
background information, methods used, results and future directions, see Research Program
