Metabolic Re-wiring Promotes Amyloid Formation in Huntington's Disease Sai Manohar Thota1, Sai Sanwid Pradhan1, Joshy EV2, Bhavana N2, Sankar N2, Sunil HV3, Venketesh S1 1Sri Sathya Sai Institute of 1Higher Learning and 2Higher Medical Sciences, Prasanthi Nilayam and 3Mazumdar Shaw Cancer Center, Bangalore, India
Huntington's disease (HD) is an inherited, neurodegenerative disorder caused due to expanded CAG repeats on Huntingtin (HTT) gene. Although earlier studies have shown metabolic alterations such as mitochondrial dysfunction to be associated with HD, their underlying mechanism of action is unknown. We hypothesize key metabolic alterations promote amyloidogenesis in HD.
MR Spectroscopy and [18F]FDG-PET on a pilot group of clinically verified HD patients with HTT allele (>39 CAG repeats) showed reduced NAA/Creatine ratio, mildly elevated lactate, and glucose hypometabolism in the caudate and putamina. In silico analysis of gene expression data from human HD brain and yeast models (25Q and 103Q HTT) revealed altered expression of genes in glycolysis/gluconeogenesis, pyruvate metabolism, and TCA cycle, among others, highlighting metabolic-rewiring in HD. Mass spectrometry-based metabolome profiling in HD yeast model containing gain-of-toxic-function of HTT (25Q: control, and 72Q, 103Q: mutant HTT), showed significant alterations in 17 metabolites in 72Q and 103Q versus 25Q. These included metabolites in the bioenergetic pathways such as lactate, succinate, glutamine and stearic acid. Interestingly, perturbation of mitochondrial function and hence NAD accumulation and ROS levels, using addition of Azide or genetic knockout of Mitochondrial Pyruvate Carrier (MPC1) or addition of pyruvate or lactate, all resulted in elevated amyloidogenesis. This was mitigated by thymine-lipoic acid (used clinically for treatment of pyruvate related metabolic disorders) that promote pyruvate utilization via NAD-dependent pyruvate dehydrogenase in the mitochondria. Furthermore, addition of Nicotinic acid, a precursor for NAD synthesis, diminished amyloid formation. In contrast, addition of hydrogen peroxide, a ROS generating agent enhanced amyloid formation that were diminished using antioxidants such as N-acetylcysteine.
Taken together, our data for the first time demonstrates that key alterations in bio-energetic metabolites resulting in mitochondrial dysfunction and impaired pyruvate metabolism could affect NAD levels, that together impact amyloid formation in HD.
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