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Cellular and Molecular Life Sciences

, Volume 69, Issue 16, pp 2691–2715 | Cite as

Role of the ubiquitin–proteasome system in nervous system function and disease: using C. elegans as a dissecting tool

  • Márcio S. Baptista
  • Carlos B. Duarte
  • Patrícia Maciel
Review

Abstract

In addition to its central roles in protein quality control, regulation of cell cycle, intracellular signaling, DNA damage response and transcription regulation, the ubiquitin–proteasome system (UPS) plays specific roles in the nervous system, where it contributes to precise connectivity through development, and later assures functionality by regulating a wide spectrum of neuron-specific cellular processes. Aberrations in this system have been implicated in the etiology of neurodevelopmental and neurodegenerative diseases. In this review, we provide an updated view on the UPS and highlight recent findings concerning its role in normal and diseased nervous systems. We discuss the advantages of the model organism Caenorhabditis elegans as a tool to unravel the major unsolved questions concerning this biochemical pathway and its involvement in nervous system function and dysfunction, and expose the new possibilities, using state-of-the-art techniques, to assess UPS function using this model system.

Keywords

Ubiquitylation E1 E2 E3 De-ubiquitylase Nematode Neurodevelopment Neurodegeneration Synaptic plasticity Neurological disease 

Abbreviations

17-AAG

17-(Allylamino)-17-demethoxygeldanamycin

17-DMAG

17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin

AD

Alzheimer’s disease

AMPAr

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

AMSH

Associated molecule with the SH3 domain of STAM

APC

Anaphase-promoting complex

Arc

Activity-regulated cytoskeleton-associated protein

ASDs

Autism spectrum disorders

ATX-3

Ataxin-3

CDT-1

Chromatin licensing and DNA replication factor 1

CHIP

C terminus of Hsc70-interacting protein

CIT-K

Citron kinase

CIT-N

Citron N

CPT

Camptothecin

DLK-1

Dual-leucine zipper Kinase MAPKKK

DS

Down syndrome

DUB

Deubiquitylating enzyme

DUBs

Deubiquitylating enzymes

E1

Ubiquitin-activating enzyme

E2

Ubiquitin-conjugating enzyme

E3s

Ubiquitin ligases

ERAD

Endoplasmatic reticulum-associated degradation

GABA

Gamma-aminobutyric acid

HAUSP

Herpesvirus-associated ubiquitin-specific protease

HD

Huntington’s disease

HSNL

Hermaphrodite-specific motor neuron

Htt

Huntingtin

JAMM

Jab1/MPN domain-associated metalloisopeptidase class

LPA

L-α-lysophosphatidic acid

LTF

Long-term facilitation

mEPSCs

Miniature excitatory postsynaptic currents

MJD

Machado–Joseph disease

NGF

Nerve growth factor

OTU

Otubain protease

PAM

Protein associated with myc

PD

Parkinson’s disease

PGPH

Peptidyl-glutamyl peptide-hydrolyzing

PKA

Protein kinase A

PolyQ

Polyglutamine

PSR

Primary synapse region

RPM-1

Regulator of pre-synaptic morphology-1

REST

Repressor element 1-silencing transcription factor

RIM1

Rab3-interacting molecule 1

SCA7

Spinocerebellar ataxia type 7

SCF

Skip1-cullin-F-Box

Smurf1 and Smurf2

Smad ubiquitylation regulatory factors 1 and 2

UBB+1

Ubiquitin-B+1

UBC

Ubiquitin-conjugating catalytic fold

UCH

Ubiquitin C-terminal hydrolase

Uch37

Ubiquitin C-terminal hydrolase 37

UCH-L1

Ubiquitin C-terminal hydrolase 1

UPS

Ubiquitin–proteasome system

USP

Ubiquitin-specific protease

USP7

Ubiquitin-specific protease 7

USP-25

Ubiquitin-specific protease 25

USP-46

Ubiquitin-specific protease 46

VCP

Valosin-containing protein

Notes

Acknowledgments

The work in the authors’ laboratory is funded by Fundação para a Ciência e a Tecnologia, Portugal (PTDC/SAU-GMG/101572/2008) and (PTDC/SAU-NMC/120144/2010), and M.S.B. received a scholarship from Fundação para a Ciência e Tecnologia (SFRH/BD/47963/2008). We thank Andreia Teixeira-Castro for critical review of the manuscript.

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Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Márcio S. Baptista
    • 1
    • 2
  • Carlos B. Duarte
    • 3
    • 4
  • Patrícia Maciel
    • 1
    • 2
  1. 1.Life and Health Sciences Research Institute (ICVS), School of Health SciencesUniversity of Minho, Campus de GualtarBragaPortugal
  2. 2.PT Government Associate Laboratory, ICVS/3B’sBraga/GuimarãesPortugal
  3. 3.Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  4. 4.Department of Life SciencesUniversity of CoimbraCoimbraPortugal

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