Essential fatty acids in Huntington's disease.

摘要

Huntington's disease is an inherited neurodegenerative disorder due to a mutation in exon 1 of the Huntingtin gene that encodes a stretch of polyglutamine (polyQ) residues close to the N-terminus of the huntingtin protein. Aggregated polyQ residues are highly toxic to the neuronal cells when they enter the cell nucleus. The mechanisms by which aggregated polyQ induces neurodegeneration include the binding of abnormal huntingtin to cyclic adenosine monophosphate response element binding protein, which hampers its ability to turn on transcription of other genes; mutant huntingtin binding to the active site on the cyclic adenosine monophosphate response element binding protein, which is essential for its acetyltransferase activity and, hence, the drugs that inhibit histone deacetylase arrest polyQ-dependent neurodegeneration; and/or disrupting the ubiquitin-proteasome system. Transgenic R6/1 mice that incorporate a human genomic fragment containing promoter elements exon 1 and a portion of intron 2 of thehuntingtin gene responsible for Huntington's disease develop late-onset neurologic deficits in a manner similar to the motor abnormalities of Huntington's disease and show increased survival rates and decreased neurologic deficits when supplemented with essential fatty acids throughout life. A randomized, placebo-controlled, double-blind study has shown that highly unsaturated fatty acids are beneficial to patients with Huntington's disease. These results raise the possibility that unsaturated fatty acids may prevent or arrest polyQ aggregation, inhibit histone deacetylase, and/or activate the ubiquitin-proteasome system. In view of the encouraging results with essential fatty acids in Huntington's disease, it is proposed that their possible use in other neurodegenerative conditions need to be explored.