Aggregates of mutant huntingtin protein have been used as pathological markers for these toxic protein fragments ever since scientists discovered them several years ago in the Huntington's brain. The exact role they play in the disease is still widely debated, Li said. Some scientists believe aggregates are a byproduct of the disease and could have a protective effect by absorbing all the mutant protein together and thus reducing toxicity, while others think aggregates are the cause of Huntington's. What mystifies scientists is why the mutant proteins kill only neurons and not other cells, and why, although aggregates are present in many neurons, only certain neurons die. In collaboration with Peggy Shelbourne of the University of Glasgow, He Li, a postdoctoral fellow in Xiao-Jiang Li's group, discovered that not only are large aggregates of mutant proteins present in the nuclei of certain neuronal cells, but also that tiny aggregates are present in the axon terminals of cells corresponding to the brain regions specifically affected by Huntington's.
Axons are spiny extensions of neurons that carry brain impulses.
They contain small vesicles that store neurotransmitters and release them when a neuron is stimulated or excited, thus these vesicles are very important in neuronal communication. Li and his colleagues found that mutant huntingtin fragments affect the storage of neurotransmitters in the vesicles. The fragments of mutant proteins or their aggregates are likely to block the vesicles in the axons and thus inhibit the release of neurotransmitters. Li believes the finding also has implications for other neurodegenerative diseases resulting from similar triple-repeat genetic mutations.