The stressed synapses - Tiziana Borsello - 23/04/2021
The stressed synapses
Tiziana Borsello, Università degli Studi di Milano
Synaptopathy define key features of many of neurodegenerative and psychiatric disorders. The synaptic degeneration, which undergo to a first reversible phase of “spine dysfuncion” leading to second irreversible phase of synaptic loss/death, which will lead to dendrite retraction and progress with neuronal death. Because synaptic injury precedes neuronal death and dysfunctional synapse possess a remarkable capacity for repair and functional recovery, we focus our efforts to develop a strategy to protect synapses during this early phase of the brain pathology. However, the intracellular mechanisms regulating synaptic dysfunction in AD are currently not fully understood. We identify the c-Jun N-terminal kinase (JNK) as a key player in AD synaptopathy. We characterized the JNK role in Ab oligomer-induced synaptopathy in vitro and in vivo in post-synaptic element describing the PSD alteration mediated by JNK. Our results demonstrated that the specific JNK inhibition (D-JNKI1) protected synapsed degeneration. Importantly JNK role in the post synaptic element is double: phophorylation of PSD-95 and Tau. JNK action on PSD-95 induced it down-relulation and PSD marker alterations, while JNK hyper-phosphorylation of Tau, altered Tau and Drebrin interaction, this leads to spine dysmorphogenesis. We then focused on JNK presynaptic localization and its role at this site. We proved that presynaptic fractions contained significant amount of JNK protein and its activated form. With biochemical approaches we demonstrated the interaction between JNK Synataxin-1,2 and Snap25. We defined JNK action on the SNARE complex formation and its role in modulation of vesicle release. These data showed JNK important functional role in post and pre-synaptic element. In conclusion, all together these results set the basis to develop a JNK-base therapeutic strategy to tackle synapse degeneration.
April 23th 12.00 am