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

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.

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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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Acknowledgments

Work in the laboratories P.S. and M.D. is supported through Grants of the Deutsche Forschungsgemeinschaft (DFG: SFB877, SPP1580, GRK1459, Cluster of Excellence: Inflammation at Interfaces), the VERUM foundation and the Interuniversity Attraction Poles Program IUAP P7/16 of the Belgian Federal Science Policy Office. E.L.E. and T.S. are supported by the Academy of Finland, Biocentrum Helsinki, and Sigrid Juselius Foundation. We thank Nicolas Yeung (University of Helsinki) for his contribution to designing Fig. 1.

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Correspondence to Eeva-Liisa Eskelinen.

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P. Saftig and E.-L. Eskelinen have equal contribution.

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Damme, M., Suntio, T., Saftig, P. et al. Autophagy in neuronal cells: general principles and physiological and pathological functions. Acta Neuropathol 129, 337–362 (2015). https://doi.org/10.1007/s00401-014-1361-4

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Keywords

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