Modification of Huntington's Protein Reverses Degeneration
Acetylated mutant protein cleared from neurons
FRIDAY, April 3 (HealthDay News) -- Chemical modification of the mutant protein that accumulates in neurons in patients with Huntington's disease leads to clearance of the protein and reversal of neurodegeneration, researchers report in the April 3 issue of Cell.
Following up on previous results showing that mutant Huntingtin (Htt) interacts with the histone acetyltransferase region of a protein, Hyunkyung Jeong, from Harvard Medical School in Boston, and colleagues investigated whether Htt could be modified by acetylation and the effect of this modification on the protein and the disease.
The researchers found that the mutant, but not wild-type Htt protein, was acetylated on lysine 444 both in vitro and in vivo, including in the brains of patients with Huntington's disease. The acetylated protein was targeted to autophagosomes, significantly improving its clearance by macroautophagy and reversing neurodegeneration in both neurons and in a transgenic worm model of Huntington's disease. In contrast, mutant Htt that could not be acetylated accumulated and led to neurodegeneration in neurons and in the mouse brain, the authors note.
"These studies identify acetylation as a mechanism for removing accumulated protein in Huntington's disease, and more broadly for actively targeting proteins for degradation by autophagy," Jeong and colleagues conclude.