An insight on new roles of the proteasome complex on organelle axonal transport

OTERO MG; SAEZ T; ALLOATTI M; CROMBERG L; FALZONE T

Chicago

Congreso; Annual meeting of the Society for Neuroscience; 2015

Society for Neuroscience

Axonal transport is the neuron mechanism that ensures the correct delivery and positioning of different organelles and vesicles. Impairments of the transport machinery at different levels have been associated with abnormal protein accumulation in Alzheimer disease (AD). The observation in AD of abnormal protein accumulation at confined intracellular regions of the neuron suggests local defect in protein degradation. The ubiquitin-proteasome system (UPS) is the major route for cytosolic protein degradation and proteasome distribution throughout the neuron is necessary for normal physiological neuronal functions and is abnormal in disease. We have recently demonstrated using a novel high spatial- and temporal-resolution analysis that proteasomes have 3 different motion regimes in axons. We described the active transport of proteasomes that is dependent on motor function and to the association of membrane organelles. These novel and important results position the axonal transport of the proteasome as a relevant intracelluar mechanism that can be impaired during the progression of neurodegenerative diseases. Here we tested a pathway to improve the axonal transport of proteasomes by the overexpression of the adaptor proteasome protein ECM29 that has affinities for proteasome, motor and membranes. In addition, the role of proteasome activity in the regulation of the axonal transport dynamics of other axonal cargos was tested in condition of short proteasome inhibitions with MG132. ECM29 overexpression is capable to improve the proportions and densities of the anterograde segmental velocities of proteasomes. Moreover, Proteasome inhibition revealed a great impact on transport dynamics inducing specific reduction in proportions and velocities of movement for different cargos. Taken together, our results reinforce the relevance of our recent demonstration of the axonal transport regimes that ensure the homogenous distribution of proteasomes in neurons and suggest that proteasome activity impacts on the regulation of the axonal transport dynamics. Interestingly, we propose a mechanism to improve the distal distribution of proteasomes in synapses that can be a novel mechanism to recover the local synaptic defects in protein degradation that have been described in neurodegenerative diseases such as AD