C2-8 Suppresses Neurodegeneration in Drosophilia

HD Lighthouse Contributing Editor's Comment: 

In this article we learn more details about the discovery of the compound C2-8.

The researchers screened for compounds which inhibit aggregation of the HD protein. The Lighthouse has been following protein aggregation for years now and it's a complex story. When the aggregates were first discovered in neurons in HD mice and confirmed in people, it seemed to many as if the major pathology of HD and the strategy for its treatment had been identified -- find a way to prevent or dissolve the aggregates. However, as regular readers know, it has proved to be less simple than that. The aggregates are certainly a pathology in that the normal huntingtin's protein doesn't aggregate, but they seem to be more of a downstream result of more important problems. The cell becomes dysfunctional before the aggregates appear and dissolving them causes cell death to happen sooner.

Still, the aggregates are a clear sign that something is wrong in the cell and if a particular compound can inhibit aggregation, it might be a treatment, depending on the mechanism involved.

The researchers identified four classes of compounds that inhibited aggregation in cell models. They are sulfobenzoic acid, naphthalimide, annelated thiazole, and oxoetheyl salicylate derivatives. Of these, an analogue of sufobenzoic acid, called C2-8 proved to be the most effective in suppressing neurodegeneration in a drosophilia (fruitfly) model of HD.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 01-01-2008

Massachusetts General Hospital fruitflies

A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo

Xiaoqian Zhang, Donna L. Smith, Anatoli B. Meriin, Sabine Engemann, Deborah E. Russel, Margo Roark, Shetia L. Washington, Michele M. Maxwell, J. Lawrence Marsh, Leslie Michels Thompson, Erich E. Wanker, Anne B. Young, David E.

Polyglutamine (polyQ) disorders, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. In polyQ diseases, the pathology and death of affected neurons are associated with the accumulation of mutant proteins in insoluble aggregates. Several studies implicate polyQ-dependent aggregation as a cause of neurodegeneration in HD, suggesting that inhibition of neuronal polyQ aggregation may be therapeutic in HD patients. We have used a yeast-based high-throughput screening assay to identify small-molecule inhibitors of polyQ aggregation. We validated the effects of four hit compounds in mammalian cell-based models of HD, optimized compound structures for potency, and then tested them in vitro in cultured brain slices from HD transgenic mice. These efforts identified a potent compound (IC50 = 10 nM) with long-term inhibitory effects on polyQ aggregation in HD neurons. Testing of this compound in a Drosophila HD model showed that it suppresses neurodegeneration in vivo, strongly suggesting an essential role for polyQ aggregation in HD pathology. The aggregation inhibitors identified in this screen represent four primary chemical scaffolds and are strong lead compounds for the development of therapeutics for human polyQ diseases.

Source: Proceedings of the Nat'l Academy of Sciences of the USA. January 18, 2005 , vol. 102, no. 3:892-8