Synergistic Effects of Milk-Derived Exosomes and Galactose on alpha-Synuclein Pathology in Parkinson's Disease and Type 2 Diabetes Mellitus

Abstract

Epidemiological studies associate milk consumption with an increased risk of Parkinson's disease (PD) and type 2 diabetes mellitus (T2D). PD is an alpha-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of alpha-synuclein (alpha-syn) and aggregation of misfolded alpha-syn. In T2D, alpha-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic beta-cells. Prion-like vagal nerve-mediated propagation of exosomal alpha-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of alpha-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb alpha-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic beta-cells may enhance miRNA-148a/DNMT1-dependent overexpression of alpha-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of alpha-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic alpha-syn may spread to dopaminergic neurons and pancreatic beta-cells linking the pathogenesis of PD and T2D.