Corticogenesis is the process in which the cerebral cortex of the brain is formed during the development of the nervous system. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. The process occurs between gestational weeks seven to 18 in humans.
Alpha-synuclein and tau are abundant multifunctional neuronal proteins, and their intracellular deposits have been linked to many neurodegenerative diseases. The Alzheimer's disease is defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein.
However, accumulating evidence suggests that the presynaptic protein α-synuclein, which is usually associated with synucleinopathies like Parkinson's disease, is also involved in the pathophysiology of AD.
Despite the disease relevance, Alpha-synuclein and tau physiological roles remain elusive, as mice with knockout of either of these genes do not exhibit overt phenotypes.
Shengming Wang and colleagues from China and Japan, hypothesized functional cooperation of αSyn and tau during corticogenesis. To reveal this cooperation, they generated a mice model where αSyn and tau genes were deleted 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, loss of αSyn and tau also perturbed gliogenesis at later embryonic stage, as well as the subsequent glial expansion and maturation at postnatal brain. The expansion and maturation of macroglial cells 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.
The authors' findings provide new mechanistic insights and extend therapeutic opportunities for neurodegenerative diseases caused by aberrant αSyn and tau.