Abstract
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 knockout of either of these genes do not exhibit overt phenotypes. To reveal functional cooperation, we generated αSyn-/-tau-/- double-knockout mice and characterized the functional crosstalk 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 αSyn-/-tau-/- cortex. Additionally, the expansion and maturation of macroglial cells (astrocytes and oligodendrocytes) were suppressed in the αSyn-/-tau-/- postnatal brain, which in turn reduced the male αSyn-/-tau-/- brain size and cortical thickness to less than the control values. Our study identifies important functional cooperation of αSyn and tau during corticogenesis.
Significance Statement
Correctly understanding of the physiological functions of alpha-synuclein (αSyn) and tau in central nervous system 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-knockout 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.
Footnotes
The authors declare no competing financial interests.
We thank Ms. Miyuki Kira (Osaka Metropolitan University) and Ms. Yoriko Yabunaka (Osaka Metropolitan University) for technical supports of DNA sequencing and HPLC analysis, Mr. Hiromichi Nishimura (Osaka Metropolitan University) and Ms. Junko Hirohara (Osaka Metropolitan University) for mouse breeding. The result data were partially obtained in Research Support Platform, Osaka Metropolitan University Graduate School of Medicine. We will also thank Dr. Ayano Kawaguchi for data analysis and discussion (Nagoya University), Ms. Namiko Noguchi (Nagoya University) and Mr. Makoto Masaoka (Nagoya University) for in utero electroporation. This work was supported by JSPS KAKENHI Grants number (JP17H04047 to S.H., JP18K06936 and JP21K06821 to M.J., JP19K16525 and JP22K06887 to S.M), by AMED (JP18ek0109390 to S.H., M.J., S.M.).
