|
13 March 2003. Oxidative stress has been implicated as a factor in the neurodegeneration that leads to a variety of neurologic disorders, including Parkinson's and Huntington's diseases. Polyglutamine expansions in huntingtin are known to cause the latter, but the exact relationship between this protein and oxidative stress is unclear. A report in this week's PNAS Early Edition, from a collaborative group led by Rajiv Ratan at Beth Israel Deaconess Medical Center in Boston, Massachusetts, may provide the answer. Ratan and colleagues have found that the transcription factor Sp1, previously shown to be sequestered by huntingtin (see ARF related news story), plays a key role in protecting neurons from oxidative damage.
First author Hoon Ryu and colleagues subjected cultures of primary neurons to oxidative stress by incubating them with the glutamate analog homocysteate, which depletes them of the antioxidant glutathione, leading to cell death. When Ryu et al. examined these neurons, they found that Sp1 had been covalently modified by acetylation; cells treated with homocysteate contained more than twice the amount of acetylated SP1 than did control cells. Also adding the antioxidant deferoxamine mesylate to the cells abrogated this modification.
Acetylation has previously been linked to oxidative damage, notably through the enzyme histone deacetylase, which is also a transcriptional activator (see ARF related news story). In fact, histone deacetylase inhibitors have shown promise as potential therapeutics for Huntington's disease (see ARF related news story). When the authors added one of these inhibitors, trichostatin A (TSA), to cultured neurons, they found that acetylation of Sp1 increased significantly, and that this prevented the homocysteate-induced cell death. To connect these two observations, Ryu added Sp1 antisense oligonucleotides to the cells. This treatment reduced by about 40 percent both the expression of Sp1, and the viability of neurons treated with homocysteate and TSA, suggesting that Sp1 is indeed necessary for TSA to rescue neurons subjected to oxidative stress.
The authors propose a model whereby acetylated Sp1 is required to fully activate the transcription of proteins such as catalase and superoxide dismutase, which help the cell cope with an oxidative environment. Loss of acetylated Sp1 through the action of deacetylases, or indeed through sequestration by huntingtin, would leave the cells vulnerable to oxidative damage and death.—Tom Fagan.
Reference:
Ryu H, Lee J, Olofsson BA, Mwidau A, Deodoglu A, Escudero M, Flemington E, Azizkhan-Clifford J, Ferrante RJ, Ratan RR. Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4281-6. Abstract
|
Home
Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway.
