The Huntington''s disease (HD)
CAG repeat, encoding a polymorphic glutamine
tract in huntingtin, is inversely correlated with cellular
energy level, with alleles over 37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3-nitropropionic acid (3-NP) and, like 3-NP, mutant
huntingtin has been proposed to directly influence the mitochondrion, via interaction or decreased PGC-1 expression. We have tested this hypothesis by comparing the gene
expression changes due to mutant huntingtin accurately expressed in STHdhQ111/Q111 cells with the changes
produced by 3-NP treatment of wild-type striatal cells. In general, the HD mutation did not mimic 3-NP, although both produced a state of energy collapse that was mildly alleviated by the PGC-1-coregulated nuclear respiratory factor 1 (Nrf-1). Moreover, unlike 3-NP, the HD CAG repeat did not significantly alter mitochondrial pathways in STHdhQ111/Q111 cells, despite decreased Ppargc1a expression. Instead, the HD mutation enriched for processes linked to huntingtin normal function and Nf-B signaling. Thus, rather than a direct impact on the mitochondrion, the polyglutamine tract may modulate some aspect of huntingtin''s activity in extra-mitochondrial energy metabolism. Elucidation of this HD CAG-dependent pathway would spur efforts to achieve energy-based therapeutics in HD.
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