The goal of this proposal is to investigate whether Mint proteins are physiological regulators of synaptic vesicle and amyloid precursor protein (APP) trafficking targeted to the active zone of the presynaptic terminal of neurons. Mint1 and Mint2 are brain-specific proteins and bind with high affinity to Munc18-1, a protein required for synaptic vesicle exocytosis. The unique structure of Mint composed of an N- terminal Munc18-1 binding domain, a middle phosphotyrosine-binding (PTB) domain and two C-terminal PDZ domains, thus suggests that it may play an essential role in targeting and docking reactions of synaptic vesicles prior to exocytosis. Of particular interest, Mint proteins also bind to APP, the parent protein for amyloid protein beta4, a major component in the pathogenesis of Alzheimer's disease. Since it is not known how intracellular APP trafficking is regulated, investigating the role of Mint proteins is an important study to pursue. Therefore, the specific aims are: (1) to study the role of Mint domains by transfection of Mint deletion mutants in hippocampal neuronal cultures; (2) to study the function of Mints in mice by gene-inducible targeting using the Cre/lox recombination system.
| Ho, Angela; Morishita, Wade; Atasoy, Deniz et al. (2006) Genetic analysis of Mint/X11 proteins: essential presynaptic functions of a neuronal adaptor protein family. J Neurosci 26:13089-101 |
| Ho, Angela; Morishita, Wade; Hammer, Robert E et al. (2003) A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission. Proc Natl Acad Sci U S A 100:1409-14 |
