Synapse-to-nucleus communication: from developmental disorders to Alzheimer's disease

In the last decade several synaptonuclear protein messengers including Jacob, CRTC1, AIDA-1, ProSaP2/Shank3 and RNF10 have been identified and characterized as key players for modulation of synaptic transmission and synaptic plasticity. Activation of excitatory glutamatergic synapses leads to their shuttling from the synapse to the nucleus, mostly importin-mediated, and subsequent regulation of gene transcription needed for long lasting modifications of synaptic function. Accordingly, increasing evidences show that alterations of the activity of synaptonuclear messengers are correlated to synaptic failure as observed in different synaptopathies. Specifically, recent studies demonstrate that the modulation of the activity of synaptonuclear messengers could represent a novel molecular target in the pathogenesis of both neurodevelopmental disorders and neurodegenerative diseases such as Alzheimer's disease.