, Volume 15, Issue 11, pp 1292–1311 | Cite as

Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications

Apoptosis in the aging brain


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.


Ubiquitin/proteasome pathway Neurodegeneration Therapy Protein aggregation 



Alzheimer’s disease


Arsenite-inducible RNA-associated protein


Amyotrophic lateral sclerosis


2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid


Carboxyl terminus of Hsc 70-interacting protein


Central nervous system


Dendritic cell aggresome-like induced structures


Defective ribosomal products


Ubiquitin-activating enzyme


Ubiquitin-conjugating enzyme


Ubiquitin ligase


Gracile axonal dystrophy


Green fluorescent protein


Huntington’s disease


Heat shock protein


Light chain 3


Machado-Joseph disease


Microtubule organizing center


Nuclear factor kappa-light-chain-enhancer of activated B cells


Nuclear factor-erythroid 2-related factor 2


Proteasome activator


Parkinson’s disease


Prostaglandin J2


PTEN-induced kinase 1




Proteasome maturation protein


Proteolysis targeting chimera molecules


19S Regulatory particle, non ATP-dependent


Ubiquitin-associated domain


Ubiquitin-like domain


Ubiquitin carboxyl-terminal hydrolase-L1


Ubiquitin-domain proteins


Ubiquitin-interacting motif


Ubiquitin/proteasome pathway


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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Biological SciencesHunter College of City University of New YorkNew YorkUSA

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