Protein post-translational modification
underlies most biological processes. The dysregulation
of protein modification plays a causative role in a number
of disease states, especially the neurodegenerative diseases.
Dr. Agar's laboratory studies protein modifications that
occur during neurodegeneration and tries to understand
the role of these modifications in disease progression.
Dr. Agar is also studying the role of protein modification
in the process of memory, which can involve modifications
as subtle as conformational change. His laboratory uses
high-resolution, Fourier transform mass spectrometry (FTMS).
Dr. Agar's talk focused on Amyotrophic Lateral
Sclerosis (ALS), which is a late-onset neurodegenerative
disease that can be caused by mutations in the gene encoding
Cu-Zn superoxide dismutase (SOD-i). The oxidation of tryptophan
32 is found to be present in both as-isolated WT SOD-i
and familial ALS causing G93A SOD-i using mass spectrometry.
In his research, Dr. Agar uses mass spectrometry to determine
if there was an effect when mutated tryptophan 32 is used,
which forms a residue with a slower rate of oxidative
modification, called phenylalanine. When this experiment
is done, it is shown to:
1) decrease the cytotoxicity of the 093A mutation to
that of WT SOD-i in a cell culture model;
2) decrease the propensity of mutant SOD-i to form cytoplasmic
aggregates; and
3) increase proteasome activity.
Preventing tryptophan 32 oxidation is therefore
a potential strategy for therapeutic intervention in familial,
and potentially sporadic, ALS.
Speaker
Schedule | Reports
from Previous Years
Top of Page | Life
Sciences | Brandeis
University
