Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes

Abstract

Alzheimer disease (AD) pathology includes the accumulation of poly-ubiquitylated (also known as poly-ubiquitinated) proteins and failures in proteasome-dependent degradation. Whereas the distribution of proteasomes and its role in synaptic function have been studied, whether proteasome activity regulates the axonal transport and metabolism of the amyloid precursor protein (APP), remains elusive. By using live imaging in primary hippocampal neurons, we showed that proteasome inhibition rapidly and severely impairs the axonal transport of APP. Fluorescence cross-correlation analyses and membrane internalization blockage experiments showed that plasma membrane APP does not contribute to transport defects. Moreover, by western blotting and double-color APP imaging, we demonstrated that proteasome inhibition precludes APP axonal transport by enhancing its endo-lysosomal delivery, where β-cleavage is induced. Taken together, we found that proteasomes control the distal transport of APP and can re-distribute Golgi-derived vesicles to the endo-lysosomal pathway. This crosstalk between proteasomes and lysosomes regulates the intracellular APP dynamics, and defects in proteasome activity can be considered a contributing factor that leads to abnormal APP metabolism in AD.This article has an associated First Person interview with the first author of the paper.

First person – María Gabriela Otero

“…Our work fits perfectly with the journal scope, and our previous work that described the axonal transport properties of the proteasome complex for the first time was published in Journal of Cell Science (Otero et al, 2014). We thought it would be an excellent opportunity to complete the story with this newly discovered role of the proteasome complex in axonal transport regulation of APP.…”

Obesity and ageing: Two sides of the same coin

“…Furthermore, the ubiquitin‐proteasome system, another mechanism degrading misfolded proteins, is abnormally modulated in individuals with obesity resulting in the aggregation of macromolecules in different tissues . Both defective autophagy and proteasome dysfunction in adipose tissue, liver, pancreas, and neurons have been proposed to cause T2DM and Alzheimer disease (AD) . Although protein aggregates accumulate gradually with age, the obesity‐induced accumulation of damaged proteins, and obesity‐inhibited autophagy and ubiquitin proteasome system may speed up the cellular senescence and premature apoptosis due to dysregulated protein homeostasis.…”

Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

“…Recently, live-cell imaging in hippocampal neurons revealed that proteasomal inhibition impairs the axonal transport of APP by stimulating its trafficking to the endo-lysosomal system for cleavage. This study underlines the importance of proteasome-lysosome crosstalk and implicated proteasomal dysfunction in the abnormal APP metabolism causing axonal degeneration in some neurodegenerative diseases [302].…”