HD Lighthouse Contributing Editor's Comment: Back in 1997 when the important discovery was made that both HD patients and the HD mice had aggregates of the mutant huntingtin's protein in the affected areas of their brains, the road to a treatment for Huntington's Disease seemed clear - find a way to dissolve the aggregates and stop the disease.

Since then, it has discovered that cells experienced degeneration and cell death without the presence of aggregates. Furthermore, a recent study by Finkbeiner and colleagues showed that the HD protein inflicts its damage before aggregates form and that the aggregates bind it up and reduce the toxic effect of the HD protein in the cell. http://www.hdlighthouse.org/research/brain/updates/1100aggregates.php

So here we have a study which focuses on inhibiting aggregation. Could it lead to a treatment? I asked Dr. Marcy MacDonald about this several years ago when research started to accumulate that aggregates were not the cause of cell death. The answer is yes, this line of research is still promising because compounds which inhibit aggregation might also reduce the toxicity of the mutant protein. In other words, while the aggregates themselves are not a primary defect in HD, it could be the properties that allow the protein to clump together are toxic. This may be why neurodegeneration was arrested in the cell and fruitfly models.

Hopefully, we'll soon see some research results with the HD mice.
--Marsha L. Miller, Ph.D.
Posted to the HDL: 13 Jan 2005

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

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.

Tracked on the Lighthouse:
aggregates

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Source: Proc Natl Acad Sci U S A. 2005 Jan 10

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