PoliQ huntingtin affects CCV endocytosis by altering distribution of AP-2 in striatal neurons

BORGONOVO J; CAPELLA P; CICCHINELLI C; ROTH G; LUCAS J; SOSA MA

Villa Carlos Paz (Córdoba)

Congreso; XLIV Reunión Anual de la Sociedad Argentina de Investigación Bioquímica (SAIB); 2008

SAIB

Clathrin coated vesicle-mediated endocytosis (CCVE) is known to be a crucial mechanism by which neurons control events such as intracellular signaling, nutrient uptake and the maintainance of  synaptic transmission. In brain, CCVs are required for recycling of membrane proteins after synapsis.  Among several coat proteins, AP-2 appear to contribute to the cargo selectivity in CCVE. In turn, Huntingtin (htt) is a cytoplasmic protein that interacts with the protein HIP1 involved in vesicle trafficking. Polyglutamine expansion (poliQ) in htt is responsible for the neuronal toxicity associated with Huntington´s disease (HD). The neurophatology of HD involves a significant dysfunction and death of neurons, particularly the medium spiny neurons of the striatum. The aim of this work was to evaluate if the expression of poliQ htt alters the levels and distribution of proteins involved in CCVE. By Western blot, we evaluated the distribution of AP-2, dynamin and HIP1 between cytosol and membrane fraction from different brain areas in transgenic mice expressing poli Q htt,  with genotype of HD (HD94)  and in striatal cell lines established from wild-type and HdhQ111 kock-in embryos (Q111). We observed a significant decrease in AP-2 bound to membranes in the striatum of HD94 mice and Q111 cells.  No changes were observed in expression and distribution of the other coat proteins. Likewise, the redistribution of AP-2 to cytosol in the mutants affected endocytosis of transferrin. These results suggest that mutant htt affects the normal distribution of AP-2 and it may contributes the pathogenesis of HD, by altering CCVE of striatal neurons.