Le funzioni della proteina motrice KIF5 nel trasporto assonale e dendritico e nella memoria.

Synapse formation, maturation, and remodeling are crucial mechanisms for brain development. Given the polarized structure of neurons, most proteins required at synaptic terminals and dendrites are synthesized in the cell soma and must be sent to their final destinations via a specialized intracellular transport system. This system consists of motor proteins, kinesin and dynein, which drive the long-distance trafficking of diverse cargos along microtubules (MTs), and actin-based myosin motors, responsible for short-range cargo trafficking along actin filaments. The human genome encodes 45 kinesin genes, divided into 14 families. Among these, the kinesin-1 family includes three homologous members, KIF5A, KIF5B, and KIF5C, that show high similarity except in their C-terminal domains. KIF5B is ubiquitously expressed, whereas KIF5A and KIF5C are predominantly expressed in neurons. While kinesins are involved in the axonal transport of synaptic vesicles and synapse assembly at the presynaptic terminal, their role in dendritic transport is less understood. Originally, the three KIF5 proteins were thought to be redundant, however, recent studies suggest they underlie different functions. KIF5B knockdown leads to deficits in dendritic transport, synaptic plasticity, and memory. Conversely, KIF5C is involved in local translation, mediating structural plasticity and long-term memory. Finally, KIF5A facilitates the transport of splicing factor proline/glutamine-rich (SFPQ)-RNA granules, critical for axon survival. Given the recent intriguing ideas that emerged on the role of KIF5 proteins, the main aim of this thesis is to describe and critically discuss the experiments that led to determine their unique functions among the different homologues. Importantly, because disruptions in axonal and dendritic transport machinery have been implicated in a range of neurological disorders, including hereditary spastic paraplegia, amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), Huntington disease (HD), and epilepsy, advancing our knowledge on KIFs biology may forward the development of novel therapeutic approaches.