MPTAC Determines APP Fragmentation via Sensing Sulfur Amino Acid Catabolism

Summary Metabolic disorder has been suggested to underlie Alzheimer’s disease (AD). However, the decisive molecular linkages remain unclear. We discovered that human Molybdopterin Synthase Associating Complex, MPTAC, promotes sulfur amino acid catabolism to prevent oxidative damage from excess sulfur amino acids, which, in turn, advances fatty acid oxidation and acetyl coenzyme A (acetyl-CoA) synthesis. The association of MPTAC with Protein arginine (R) Methyltransferase 5 (PRMT5) complex and small nuclear ribonucleoprotein (SNRP) splicing factors enables SNRPs to sense metabolic states through their methylation. This promotes the splicing fidelity of amyloid precursor protein (APP) pre-mRNA and proper APP fragmentation, abnormalities of which have been observed in the platelets of AD patients. The functions of MPTAC are crucial to maintain expression of drebrin 1, which is required for synaptic plasticity, through prevention from oxidative damage. Thus, adjustment of sulfur amino acid catabolism by MPTAC prevents events that occur early in the onset of AD.