Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications
- 4 February 2010
- journal article
- review article
- Published by Springer Science and Business Media LLC in Apoptosis
- Vol. 15 (11), 1292-1311
- https://doi.org/10.1007/s10495-010-0466-z
Abstract
The ubiquitin/proteasome pathway is the major proteolytic quality control system in cells. In this review we discuss the impact of a deregulation of this pathway on neuronal function and its causal relationship to the intracellular deposition of ubiquitin protein conjugates in pathological inclusion bodies in all the major chronic neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases as well as amyotrophic lateral sclerosis. We describe the intricate nature of the ubiquitin/proteasome pathway and discuss the paradox of protein aggregation, i.e. its potential toxic/protective effect in neurodegeneration. The relations between some of the dysfunctional components of the pathway and neurodegeneration are presented. We highlight possible ubiquitin/proteasome pathway-targeting therapeutic approaches, such as activating the proteasome, enhancing ubiquitination and promoting SUMOylation that might be important to slow/treat the progression of neurodegeneration. Finally, a model time line is presented for neurodegeneration starting at the initial injurious events up to protein aggregation and cell death, with potential time points for therapeutic intervention.Keywords
This publication has 220 references indexed in Scilit:
- Immune Activation in Brain Aging and Neurodegeneration: Too Much or Too Little?Neuron, 2009
- Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative diseaseNeurobiology of Disease, 2009
- Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradationCellular and Molecular Life Sciences, 2009
- Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3The EMBO Journal, 2009
- Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomicsBioorganic & Medicinal Chemistry Letters, 2008
- Activation and inhibition of the proteasome by betulinic acid and its derivativesFEBS Letters, 2007
- A proteasome for all occasionsFEBS Letters, 2007
- Sequestosome 1/p62 – More than just a scaffoldFEBS Letters, 2006
- Oxidative stress in Parkinson's diseaseAnnals of Neurology, 2003
- Structure of 20S proteasome from yeast at 2.4Å resolutionNature, 1997