Is age-related failure of metabolic reprogramming a principal mediator in idiopathic Parkinson’s disease? Implications for treatment and inverse cancer risk

• Published in: Medical hypotheses 2016-08, Vol.93, p.154-160
• Main Author: Engel, Peter A
• Format: Article
• Language: English
• Subjects: Aging; alpha-Synuclein - metabolism; Animals; Homeostasis; Humans; Internal Medicine; Lysosomes - metabolism; Mice; Mitochondria - metabolism; Mitochondrial Degradation; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - physiopathology; Models, Theoretical; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms - complications; Neoplasms - metabolism; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - physiopathology; Oxidative Phosphorylation; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Risk; Substantia Nigra - metabolism
• ISSN: 0306-9877; 1532-2777
• DOI: 10.1016/j.mehy.2016.05.033

Abstract Idiopathic Parkinson’s disease (IPD) is a neurodegenerative disorder characterized by selective degeneration of the substantia nigra pars compacta (SNc), dorsal motor nucleus of the vagus and other vulnerable nervous system regions characterized by extensive axonal arborization and intense energy requirements. Systemic age-related depression of mitochondrial function, oxidative phosphorylation (OXPHOS) and depressed expression of genes supporting energy homeostasis is more severe in IPD than normal aging such that energy supply may exceed regional demand. In IPD, the overall risk of malignancy is reduced. Cancer is a collection of proliferative diseases marked by malignant transformation, dysregulated mitosis, invasion and metastasis. Many cancers demonstrate normal mitochondrial function, preserved OXPHOS, competent mechanisms of energy homeostasis, and metabolic reprogramming capacities that are lacking in IPD. Metabolic reprogramming adjusts OXPHOS and glycolytic pathways in response to changing metabolic needs. These opposite metabolic features form the basis of a two component hypothesis. First, that depressed mitochondrial function, OXPHOS deficiency and impaired metabolic reprogramming contribute to focal energy failure, neurodegeneration and disease expression in IPD. Second, that the same systemic metabolic deficits inhibit development and proliferation of malignancies in IPD. Studies of mitochondrial aging, familial PD (FPD), the lysosomal storage disorder Gaucher’s disease (GD), PD cybrids, the mitochondrial cytopathies, and disease-related metabolic reprogramming both in IPD and cancer provide support for this model.