SIRT2 Inhibition Not a Promising Therapeutic Strategy
In 2010, we reported on a study which proposed that SIRT2 inhibition be explored as a potential treatment for Huntington’s Disease based on results with striatal cell, drosophila (fruitfly) and c. elegans (flatworm) models. Sirtuins are protein deacetylase enzymes, biological molecules that remove acetyl groups from lysine amino acids in proteins for the purpose of regulating biological pathways. The name sirtuin comes from the Silent Information Regulator gene 2 (Sir2), a gene which is associated with longevity in yeast and invertebrates. There are seven sirtuins in mammals. SIRT1 inhibition is in clinical trials for HD in Europe.
In the 2010 study, collaborators from the University of California at Irvine, Massachusetts General Institute for Neurodegenerative Disease, the Brain Mind Institute in Switzerland and other labs showed that inhibiting SIRT2 improved three models of HD: striatal cells, drosophila and c. elegans. Investigation with striatal cell models showed elevated levels of cellular sterols which were reduced with the administration of the SRIT2 inhbitors. Since earlier research by Dr. Elena Cattaneo and others had shown that cholesterol homeostasis is disturbed in HD, this was thought to be the mechanism by which SIRT2 worked. However, this issue is complex. Cellular sterol levels are known to be normal not elevated early on and then decline over time with HD and it is unknown whether this is pathological or a compensatory mechanism. Cholesterol is very important for brain function and even small disturbances in its homeostasis can be problematic.
The next step in the research was to explore this treatment possibility in an HD mouse model and learn more about mechanism if SIRT2 inhibition continues to be effective. A different team of researchers conducted a new study with the R6/2 mice and concluded that SIRT2 inhibition is not a promising therapeutic target. Dr. Gillian Bates and colleagues crossed R6/2 mice with SIRT2 gene knockouts or partial knockouts. In this way, they would be able to tell if any effects were actually a result of SIRT2 reduction rather than off target effects of the drugs that inhibit SIRT2.
They found that genetic reduction or depletion of SIRT2 has no effect on HD progression as measured by a variety of tests: rotarod performance, grip strength, and spontaneous movement. Brain weight Dr. Gillian Bates loss was not improved.
SIRT2 inhibition did result in body weight gain for the mice but this was independent of HD disease progression since both HD and non-HD SIRT2 knockout mice gained the weight.
They also found that genetic depletion of SIRT2 did not reduce either the HD protein aggregate load or the amount of soluble HD protein. Further, genetic depletion of SIRT2 had no effect on cholesterol biosynthesis enzymes, nor did the administration of pharmaceutical inhibitors in R6/2 mice.
The authors conclude, “This study demonstrates that SIRT2 does not modify disease progression in R6/2 mice and should not be prioritised as a therapeutic target for HD.” While this is disappointing, it is still a valuable finding. With more than two dozen potential treatments in the pipeline and limited resources (time, volunteers, and funds), it is critical that the most promising potential treatments be considered for clinical trials. This study and others like it are important in accomplishing this goal and finding safe and effective treatments for the HD community.
Anna Bobrowska, Gizem Donmez, Andreas Weiss, Leonard Guarente and Gillian Bates. “SIRT2 Ablation Has No Effect on Tubulin Acetylation in Brain, Cholesterol Biosynthesis or the Progression of Huntington’s Disease Phenotypes In Vivo“ PLoS ONE 2012;7(4):e34805. Epub 2012 Apr 12.
– Marsha L. Miller, Ph.D., May 6, 2012