| First Author | Wang S | Year | 2022 |
| Journal | J Neurosci | Volume | 42 |
| Issue | 37 | Pages | 7031-7046 |
| PubMed ID | 35906071 | Mgi Jnum | J:333924 |
| Mgi Id | MGI:7443262 | Doi | 10.1523/JNEUROSCI.0396-22.2022 |
| Citation | Wang S, et al. (2022) Functional Cooperation of alpha-Synuclein and Tau Is Essential for Proper Corticogenesis. J Neurosci 42(37):7031-7046 |
| abstractText | Alpha-synuclein (alphaSyn) 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 alphaSyn(-/-)tau(-/-) double-knock-out mice and characterized the functional cross talk between these proteins during brain development. Intriguingly, deletion of alphaSyn 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 alphaSyn(-/-)tau(-/-) cortex. Additionally, the expansion and maturation of macroglial cells (astrocytes and oligodendrocytes) were suppressed in the alphaSyn(-/-)tau(-/-) postnatal brain, which in turn reduced the male alphaSyn(-/-)tau(-/-) brain size and cortical thickness to less than the control values. Our study identifies important functional cooperation of alphaSyn and tau during corticogenesis.SIGNIFICANCE STATEMENT Correct understanding of the physiological functions of alphaSyn and tau in CNS is critical to elucidate pathogenesis involved in the etiology of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. We show here that alphaSyn and tau are cooperatively involved in brain development via maintenance of progenitor cells. alphaSyn and tau double-knock-out mice exhibited an overproduction of early born neurons and accelerated neurogenesis at early corticogenesis. Furthermore, loss of alphaSyn and tau also perturbed gliogenesis at later embryonic stage, as well as the subsequent glial expansion and maturation at postnatal brain. Our findings provide new mechanistic insights and extend therapeutic opportunities for neurodegenerative diseases caused by aberrant alphaSyn and tau. |
