'Inhibitor' Molecule Helps ALS Mice be Stronger, Live Longer

by Amy Madsen on Thu, 2011-07-28 13:47

Treatment with the HDAC inhibitor trichostatin A delayed disease onset and increased survival time in SOD1 research mice

Article Highlights:
  • Mice with a disease resembling human ALS received injections of trichostatin A, a histone deacetylase (HDAC) inhibitor.
  • HDAC inhibitors keep "read me" signals called acetyl groups attached to genes, making the genes available to be read by the cell and used for protein production.
  • Mice treated with TSA had more surviving nerve cells and nerve-muscle junctions, less muscle atrophy, greater strength and increased survival time compared to their untreated counterparts.

An experimental compound called trichostatin A (TSA) has been shown to improve nerve-cell survival, increase strength and muscle weight, and result in longer life span in mice with a disease resembling ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

TSA belongs to a family of chemical compounds called HDAC (histone deacetylase) inhibitors, which keep "read me" signals called acetyl groups attached to genes. The presence of the acetyl groups causes cells to interpret genetic instructions as "open" and ready to be read and used in protein production, rather than "closed," which results in the silencing of the gene.

The findings were reported online June 20, 2011, by a team of scientists, including MDA-supported Chien-Ping Ko at the Department of Biological Sciences, University of Southern California in Los Angeles.

The researchers say their results provide data that support testing of HDAC inhibitors in ALS.

TSA treatment conferred multiple benefits in SOD1 mice

Researchers injected TSA into the abdomens of mice carrying mutated human SOD1 genes (one cause of ALS in humans), beginning when the mice were 90 days old. The 90-day time point was chosen because it coincides with the appearance of disease symptoms in the mice, and so mimics what likely will be the case with humans, who generally learn they have ALS only after symptom onset.

The injections were administered five days a week, until the mice reached end stage at around 120 days old. A control group of SOD1 mice received placebo injections.

Upon examination, the research team observed that, compared to their untreated counterparts, the TSA-treated mice:

  • had better survival of motor neurons (muscle-controlling nerve cells that are lost in ALS);
  • demonstrated less degeneration of the long nerve-cell fibers called axons, through which neurons transmit and receive signals;
  • experienced less muscle atrophy;
  • had less of the scarring that forms in the wake of motor neuron death (a process called gliosis); and
  • exhibited reduced numbers of ALS-associated neural "disconnects," called denervations, in neuromuscular junctions. (Neuromuscular junctions are composed of a special type of tissue through which signals between nerve cells and muscles pass.) 

Also observed in the TSA-treated mice was an increase in levels of the glutamate transporter GLT1 in the spinal cord. More GLT1 proteins translated to a reduction of glutamate excitotoxicity, a toxic buildup of the neurotransmitter glutamate that can lead to motor neuron damage and death. (Research has shown that people with ALS have raised levels of glutamate in the brain and spinal cord.)

Functional benefits included improved motor function as measured by grip strength and performance tests that evaluated endurance, balance and coordination.

Furthermore, TSA treatment significantly increased the average survival time from disease onset to end stage and prolonged overall life span.

HDAC inhibitors may have a role to play in ALS therapies

The researchers chose to test TSA, as opposed to other HDAC inhibitors, based on results reported in previous non-ALS studies. TSA has proven to be a potent inhibitor of many of the HDACs, and its effects have been observed in a range of different cell types. This increased the likelihood of uncovering the various potentials of HDAC inhibitors in ALS.

Increasing evidence suggests that multiple conditions and processes play a role in the ALS disease process. A number of these conditions and processes were improved by treatment with TSA in the SOD1 mouse in this study.

The ability of TSA and other HDAC inhibitors to reactivate ("turn on") genes that may be abnormally silenced in ALS could allow cellular machinery to produce necessary proteins and activate crucial biological pathways affected by possible contributors to the ALS disease process.

Meaning of TSA results for people with ALS

HDAC inhibitors may be promising drug candidates for ALS, the study authors concluded, due to their effects on multiple targets implicated in the disease.

Further testing is needed to determine what effects HDAC inhibitors may have in ALS, and whether other HDAC inhibitors can be aimed at more specific targets than the large number affected by TSA.

The data from this study support the testing of HDAC inhibitors in ALS.

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