Ubiquitin Proteasome System (UPS) inhibition induce retrograde axonal transport reductions by impairing the endosomal-lysosomal pathway (ELP)

OTERO MG; CROMBERG L; FALZONE T

Huerta Grande,

Congreso; XXVI Congreso de la Sociedad Argentina de Neurociencias; 2011

SAN

Alzheimer´s disease (AD), the most frequent neurodegenerative disease, accounts for 70 % of dementias. Accumulation of aberrant and polyubiquitinated proteins in synapses and distrophic neurites in AD suggest that proteins degradation mechanisms might be impared. The two major routes of intracellular protein degradation are the ubiquitin-proteasome system (UPS) and the endo-Lysosome pathway (ELP). Consequently it is important to understand how UPS is delivered to synapses and the role of UPS activity in synaptic ELP regulation. To test for the axonal transport of UPS we performed live imaging experiments of a fluorescent proteasome subunit (α4-YFP) revealing processive anterograde and retrograde particulated movement with motor-dependent speeds. To test for therole of UPS activity in  transport regulation we inhibited the proteasome and observed a selective decreased in retrograde transport. Double color movies of α4-YFP and Lysotracker-RED suggest that retrograde moving UPS is associated with lysosomes. Subcellular fractionation in sucrose density gradients after UPS inhibition revealed impairments in EEA1 early endosomal membranes. Moreover, UPS inhibition induced a decrease in retrograde axonal transport and lysosomes axonal densities . Our results revealed that defects in UPS activity impairs the formation of endo-lysosomal vesicles and reduce lysosome retrograde transport suggesting a relevant crosstalk between synaptic UPS and ELP with important implications in AD pathologies.