Apoptosis

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

Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications

Apoptosis in the aging brain

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

Ubiquitin/proteasome pathway Neurodegeneration Therapy Protein aggregation 

Abbreviations

AD

Alzheimer’s disease

AIRAP

Arsenite-inducible RNA-associated protein

ALS

Amyotrophic lateral sclerosis

CDDO

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

CHIP

Carboxyl terminus of Hsc 70-interacting protein

CNS

Central nervous system

DALIS

Dendritic cell aggresome-like induced structures

DriPs

Defective ribosomal products

E1

Ubiquitin-activating enzyme

E2

Ubiquitin-conjugating enzyme

E3

Ubiquitin ligase

Gad

Gracile axonal dystrophy

GFP

Green fluorescent protein

HD

Huntington’s disease

Hsp

Heat shock protein

LC3

Light chain 3

MJD

Machado-Joseph disease

MTOC

Microtubule organizing center

NF-κB

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

Nrf2

Nuclear factor-erythroid 2-related factor 2

PA

Proteasome activator

PD

Parkinson’s disease

PGJ2

Prostaglandin J2

PINK1

PTEN-induced kinase 1

PolyQ

Polyglutamine

POMP

Proteasome maturation protein

PROTACS

Proteolysis targeting chimera molecules

Rpn

19S Regulatory particle, non ATP-dependent

UBA

Ubiquitin-associated domain

UBL

Ubiquitin-like domain

UCH-L1

Ubiquitin carboxyl-terminal hydrolase-L1

UDP

Ubiquitin-domain proteins

UIM

Ubiquitin-interacting motif

UPP

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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