Alzheimer's disease (AD) is characterized by accumulation of two misfolded and 
aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular 
systems responsible for clearance of misfolded and aggregated proteins, the 
lysosomal and the proteasomal, have been shown to be malfunctioning in the aged 
brain and more so in patients with neurodegenerative diseases, including AD. 
This malfunction could be contributing to β-amyloid and tau accumulation, 
eventually aggregating in plaques and tangles. We have investigated the impact 
of decreased proteasome activity on tau phosphorylation as well as on 
microtubule stability and transport. To do this, we used our recently developed 
neuronal model where human SH-SY5Y cells obtain neuronal morphology and function 
through differentiation. We found that exposure to low doses of the proteasome 
inhibitor MG-115 caused tau phosphorylation, microtubule destabilization and 
disturbed neuritic transport. Furthermore, reduced proteasome activity activated 
several proteins implicated in tau phosphorylation and AD pathology, including 
c-Jun N-terminal kinase, c-Jun and extracellular signal-regulated protein kinase 
(ERK) 1/2. Restoration of the microtubule transport was achieved by inhibiting 
ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun 
reversed the proteasome inhibition-induced tau phosphorylation. Taken together, 
this study suggests that a decrease in proteasome activity can, through 
activation of c-Jun and ERK 1/2, result in several events related to 
neurodegenerative diseases. Restoration of proteasome activity or modulation of 
ERK 1/2 and c-Jun function can open new treatment possibilities against 
neurodegenerative diseases such as AD.