Neurons relying heavily on the ubiquitin-proteasome system (UPS) for protein clearance are vulnerable to proteasomal dysfunction.
The UPS degrades most intracellular proteins. Neurons are particularly dependent on UPS due to:
- Long lifespan
- Post-mitotic state
- High protein turnover at synapses
- Alpha-synuclein accumulation
- Proteasome subunit reductions
- Early vulnerability in PD
- High translational burden
- Protein aggregate accumulation
- Selective vulnerability in ALS
- Proteasome activity declines with age
- Tau accumulation
- Early dysfunction in AD
- Age-related decline
- Oxidative damage to subunits
- Inhibitory aggregates
- E3 ligase dysfunction
- Deubiquitinating enzyme issues
- Polyubiquitin chain accumulation
- Proteasome trapping
- Functional proteasome reduction
- Spreading pathology
- Natural compounds (EGCG)
- Synthetic small molecules
- Novel peptide activators
- Enhanced macroautophagy
- Chaperone-mediated autophagy
- Pharmacological induction
- Proteasome in neurodegeneration (2022)
- UPS and neuronal vulnerability (2021)