Brain Transcriptomic, Metabolic and Mitohormesis Properties Associated with N-Propargylglycine Treatment: A Prevention Strategy Against Neurodegeneration

• DOI: 10.2139/ssrn.4527814
• Publication Date: 2023-08-07T14:26:27Z
• Authors: Fadzai Termayi; Joanna Bons; Madeleine KD Scott; Gary K. Scott; Ashley Loureiro; Alejandro Lopez-R...; Birgit Schilling; Lisa Ellerby; Christopher C. Benz
• Keywords: Proline dehydrogenase

Introduction: There is an urgent need for new or repurposed therapeutics that protect against significantly delay the clinical progression of neurodegenerative diseases such as Huntington’s disease (HD), Parkinson’s and Alzheimer’s disease. In particular, preclinical studies are needed well tolerated brain-penetrating small molecules capable mitigating proteotoxic mitochondrial processes hallmarks these diseases. We identified a unique suicide inhibitor proline dehydrogenase (Prodh), Npropargylglycine (N-PPG), which has anticancer brain-enhancing mitohormesis properties, we hypothesize induction by N-PPG protects diseases.Methods: carried out series mouse designed to: i) compare brain metabolic responses while on oral treatment (50 mg/kg, 9-14 days) B6CBA wildtype (WT) short-lived transgenic R6/2 (HD) mice; ii) evaluate potential systemwide stress rebound in WT mice 2 months after cessation extended higher doses (100-200 mg/kg x 60 days).Results: HD showed comparable global evidence induced characterized Prodh protein decay increased expression chaperone Yme1l1 protease proteins. Interestingly, transcriptional analysis (RNAseq) partial normalization whole transcriptomes toward those mice. Comprehensive metabolomic profiles performed control treated blood, brain, kidney samples revealed expected tissue increases levels both mice, accompanied surprising parallel hydroxyproline sarcosine. Two dose treatments, brains robust transcriptome responses, altered blood amino acid-related metabolites.Discussion: Our findings point to penetrating mitohormesis-inducing drug candidate, N-PPG, provide rationale application insights supporting its further testing various models loss proteostasis.