Department of Genetic Disease Research, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan.
Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
J Neurosci. 2022 Sep 14;42(37):7031-7046. doi: 10.1523/JNEUROSCI.0396-22.2022. Epub 2022 Jul 29.
Alpha-synuclein (αSyn) 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 αSyntau double-knock-out mice and characterized the functional cross talk between these proteins during brain development. Intriguingly, deletion of αSyn 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 αSyntau cortex. Additionally, the expansion and maturation of macroglial cells (astrocytes and oligodendrocytes) were suppressed in the αSyntau postnatal brain, which in turn reduced the male αSyntau brain size and cortical thickness to less than the control values. Our study identifies important functional cooperation of αSyn and tau during corticogenesis. Correct understanding of the physiological functions of αSyn 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 αSyn and tau are cooperatively involved in brain development via maintenance of progenitor cells. αSyn and tau double-knock-out mice exhibited an overproduction of early born neurons and accelerated neurogenesis at early corticogenesis. Furthermore, loss of αSyn 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 αSyn and tau.
α-突触核蛋白（αSyn）和 tau 是丰富的多功能神经元蛋白，其细胞内沉积物与许多神经退行性疾病有关，包括阿尔茨海默病和帕金森病。尽管与疾病相关，但它们的生理作用仍不清楚，因为敲除这些基因中的任何一个的小鼠都没有表现出明显的表型。为了揭示功能上的合作，我们生成了αSyn-tau 双敲除小鼠，并在大脑发育过程中研究了这些蛋白之间的功能串扰。有趣的是，αSyn 和 tau 的缺失减少了 Notch 信号，并加速了早期胚胎阶段 G2 期的核周迁移。这显著改变了祖细胞增殖和神经发生之间的平衡，导致早期出生的神经元过度产生，并增强了神经发生，从而在雌雄两性胚胎期大脑增大。另一方面，皮质发生中期神经祖细胞数量的减少减少了αSyntau 皮质中的随后的神经胶质发生。此外，αSyntau 出生后大脑中的大胶质细胞（星形胶质细胞和少突胶质细胞）的扩张和成熟受到抑制，这反过来又使雄性αSyntau 大脑的大小和皮质厚度减小到低于对照值。我们的研究确定了αSyn 和 tau 在皮质发生过程中的重要功能合作。正确理解αSyn 和 tau 在中枢神经系统中的生理功能对于阐明包括阿尔茨海默病和帕金森病在内的神经退行性疾病的发病机制至关重要。我们在这里表明，αSyn 和 tau 通过维持祖细胞共同参与大脑发育。αSyn-tau 双敲除小鼠在早期皮质发生时表现出早期出生神经元的过度产生和神经发生的加速。此外，αSyn 和 tau 的缺失也在胚胎后期扰乱了神经胶质发生，以及随后在出生后大脑中的神经胶质扩张和成熟。我们的发现为异常的αSyn 和 tau 引起的神经退行性疾病提供了新的机制见解和扩展治疗机会。
