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

Epidemiological studies associate milk consumption with an increased risk of Parkinson's disease (PD) and type 2 diabetes mellitus (T2D). PD is an -synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of -synuclein (-syn) and aggregation of misfolded -syn. In T2D, -syn promotes co-aggregation with islet amyloid polypeptide in pancreatic -cells. Prion-like vagal nerve-mediated propagation of exosomal -syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of -syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb -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 -cells may enhance miRNA-148a/DNMT1-dependent overexpression of -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 -syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic -syn may spread to dopaminergic neurons and pancreatic -cells linking the pathogenesis of PD and T2D.