Functional Cooperation of a-Synuclein and Tau Is Essential for Proper Corticogenesis

Abstract

Alpha-synuclein (aSyn) and tau are abundant multifunctional neuronal proteins, and their intracellular deposits have been linked to many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Despite the disease relevance, their physiological roles remain elusive, as mice with knock-out of either of these genes do not exhibit overt phenotypes. To reveal functional cooperation, we generated aSyn2/2tau2/2 double-knock-out mice and characterized the functional cross talk between these proteins during brain development. Intriguingly, deletion of aSyn and tau reduced Notch signaling and accelerated interkinetic nuclear migration of G2 phase at early embryonic stage. This significantly altered the balance between the proliferative and neurogenic divisions of progenitor cells, resulting in an overproduction of early born neurons and enhanced neurogenesis, by which the brain size was enlarged during the embryonic stage in both sexes. On the other hand, a reduction in the number of neural progenitor cells in the middle stage of corticogenesis diminished subsequent gliogenesis in the aSyn2/2tau2/2 cortex. Additionally, the expansion and maturation of macroglial cells (astrocytes and oligodendrocytes) were suppressed in the aSyn2/2tau2/2 postnatal brain, which in turn reduced the male aSyn2/2tau2/2 brain size and cortical thickness to less than the control values. Our study identifies important functional cooperation of aSyn and tau during corticogenesis.