FIGURE 8.

Hypothesis on the function of EFhd2 in the brain. EFhd2 inhibits kinesin-mediated anterograde microtubule transport in neurons. This could also involve physical or functional interaction with the microtubule binding protein tau. It also negatively regulates the formation of synapses either directly through its effect on actin remodeling and a potential function in growth cones other than neurite outgrowth or indirectly through its negative impact on microtubule transport. EFhd2 is a Ca²⁺-binding protein, and its function is regulated by intracellular Ca²⁺. Pathologically elevated Ca²⁺ might therefore impact on EFhd2 function. Ca²⁺ is furthermore involved in signaling mechanisms activating the Cdk5 protein kinase, which inhibits EFhd2 by phosphorylation of residues relevant for its Ca²⁺-binding activity. Pathologically elevated Ca²⁺ levels and aberrant activation of Cdk5 have previously been described in neurodegenerative diseases. Changes in EFhd2 expression as well as synapse loss are associated with dementia and other neurodegenerative diseases affecting the frontal cortex. EFhd2 might be involved in processes such as synaptic pruning or morphologic plasticity in this brain region, and its loss might have a profound impact on the balance of synapse maintenance and exacerbate or be a sign of synaptic pathology.