Arylamine N-acetyltransferase-1 reveals a subpopulation of ALS patients with altered metabolic capacity

Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease characterised by metabolic changes at onset and throughout disease progression. Here, we investigate the role of arylamine N-acetyltransferase 1 (NAT1), a cytosolic protein associated with mitochondrial function, in ALS. We demonstrate that expression of the murine homolog (mNat2) increases in skeletal muscle of SODG93A mice, but not control animals, at onset of symptoms and remains elevated until end stage of the disease. Measurement of mitochondrial respiration in peripheral blood mononuclear cells of patients with ALS identified patient sub-populations with low and high metabolic potential, which was strongly associated with NAT1 activity. Those patients with high NAT1 activity had elevated basal respiration, ATP production, mitochondrial reserve, and aerobic glycolysis. NAT1 predicted increased whole body metabolic index, which may be clinically significant as these patients show increased functional decline and shorter survival. NAT1 may be a novel target in those patients with elevated activity

Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration

“…30,31 Aside from their role as experimental tools to study NAT1 function, NAT1 inhibitors may be useful in the future for the treatment of various hypermetabolic diseases. For example, high NAT1 expression in patients with amyotrophic lateral sclerosis correlates with a hypermetabolic state, 32 which predicts poorer outcomes. 33 Patients with high NAT1 show a significantly shorter survival, 34 suggesting that inhibition of NAT1 may have therapeutic potential.…”