Abstract
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-1α 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-1α-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-κB 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.
Highlights
The CAG trinucleotide repeat in the Huntington’s disease gene (HD) is highly polymorphic in humans, with alleles ranging from ;6 to .100 units encoding a variable polyglutamine tract in huntingtin, a large (.350 kDa) HEAT domain protein [1]
While mutant huntingtin and 3-nitropropionic acid (3-NP) both elicited energy starvation, the gene responses to the HD mutation, unlike the responses to 3-NP, did not highlight damage to mitochondria, but instead revealed effects on huntingtin-dependent processes
Recent findings, including studies in STHdhQ111/Q111 striatal cells, with a knock-in juvenile onset CAG repeat accurately expressed as endogenous huntingtin with 111 glutamines [18], suggested that mutant huntingtin may influence mitochondrial biogenesis/function by decreasing Ppargc1a transcription [19,20]
Summary
Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism. 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-1a expression. 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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