Acta Neuropathologica

, Volume 129, Issue 3, pp 337–362 | Cite as

Autophagy in neuronal cells: general principles and physiological and pathological functions

  • Markus Damme
  • Taina Suntio
  • Paul Saftig
  • Eeva-Liisa Eskelinen
Review

Abstract

Autophagy delivers cytoplasmic components and organelles to lysosomes for degradation. This pathway serves to degrade nonfunctional or unnecessary organelles and aggregate-prone and oxidized proteins to produce substrates for energy production and biosynthesis. Macroautophagy delivers large aggregates and whole organelles to lysosomes by first enveloping them into autophagosomes that then fuse with lysosomes. Chaperone-mediated autophagy (CMA) degrades proteins containing the KFERQ-like motif in their amino acid sequence, by transporting them from the cytosol across the lysosomal membrane into the lysosomal lumen. Autophagy is especially important for the survival and homeostasis of postmitotic cells like neurons, because these cells are not able to dilute accumulating detrimental substances and damaged organelles by cell division. Our current knowledge on the autophagic pathways and molecular mechanisms and regulation of autophagy will be summarized in this review. We will describe the physiological functions of macroautophagy and CMA in neuronal cells. Finally, we will summarize the current evidence showing that dysfunction of macroautophagy and/or CMA contributes to neuronal diseases. We will give an overview of our current knowledge on the role of autophagy in aging neurons, and focus on the role of autophagy in four types of neurodegenerative diseases, i.e., amyotrophic lateral sclerosis and frontotemporal dementia, prion diseases, lysosomal storage diseases, and Parkinson’s disease.

Keywords

Autophagosome Lysosome Chaperone-mediated autophagy Neurogenesis Aging Neurodegeneration FTD/ALS Prion disease Lysosomal storage disease Parkinson’s disease 

Abbreviations

AAA+-ATPase

ATPase associated with diverse cellular activities

ALS

Amyotrophic lateral sclerosis

AMBRA1

Activating molecule in beclin 1-regulated autophagy

AMPK

AMP-activated protein kinase

ATF6

Activating transcription factor 6

ATG

Autophagy-related

BECN1

Beclin 1

BNIP3

BCL2/adenovirus E1B 19 kDa interacting protein 3

CHMP2B

Charged multivesicular protein 2B

CMA

Chaperone-mediated autophagy

CNS

Central nervous system

DAP1

Death-associated protein 1

DFCP1

Double FYVE-containing protein 1

DRG

Dorsal root ganglion

ESCRT-III

Endosomal sorting complex required for transport-III

ER

Endoplasmic reticulum

ERK2

Extracellular signal-regulated kinase 2

FIP200

200 kDa FAK family kinase-interacting protein

FTD

Frontotemporal dementia

GFP

Green fluorescent protein

GTPase

Guanosine triphosphatase

HIF

Hypoxia-inducible factor

HSC70

Heat shock cognate protein of 70 kDa

IRE1

Serine/threonine-protein kinase/endoribonuclease protein

LAMP

Lysosomal associated membrane protein

LC3/MAP1-LC3

Microtubule associated protein 1 light chain 3

LRRK2

Leucine-rich repeat kinase 2

LSD

Lysosomal storage disorder

MEF2D

Myocyte enhancer factor 2D

ML-II

Mucolipidosis type II

NCL

Neuronal ceroid lipofuscinosis

NPC

Niemann–Pick C

mTOR

Mammalian target of rapamycin

mTORC1

mTOR complex 1

MVB

Multivesicular body

OPTN

Optineurin

PD

Parkinson’s disease

PERK

Protein kinase-like ER kinase

PI3P

Phosphatidyl inositol 3-phosphate

PI3KC3

Phosphatidyl inositol 3-kinase class 3

PKC

Protein kinase C

POMC

Pro-opiomelanocortin

RAPTOR

Regulatory associated protein of mTOR)

RB1CC1

RB1-inducible coiled-coil 1

REST

Repressor element 1 silencing transcription factor

Rheb

Ras homolog enriched in brain

ROS

Reactive oxygen species

SNARE

Soluble N-ethyl-maleimide-sensitive factor attachment protein receptor

SOD

Superoxide dismutase

SQSTM1

Sequestosome 1

TDP-43

Tar-DNA binding protein 43

TFEB

Transcription factor EB

TSC

Tuberous sclerosis complex

UBA

Ubiquitin-binding domain

UBQLN2

Ubiquilin 2

ULK1

Unc-51-like kinase 1

UPR

Unfolded protein response

V-ATPase

Vacuolar ATPase

VCP

Valosin-containing protein

WIPI

WD repeat domain, phosphoinositide interacting

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Markus Damme
    • 1
  • Taina Suntio
    • 2
  • Paul Saftig
    • 1
  • Eeva-Liisa Eskelinen
    • 2
  1. 1.Biochemical InstituteUniversity of KielKielGermany
  2. 2.Department of BiosciencesUniversity of HelsinkiHelsinkiFinland

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