Molecular Neurobiology

, Volume 53, Issue 8, pp 5542–5574 | Cite as

Iron and Neurodegeneration: Is Ferritinophagy the Link?

  • Giorgio Biasiotto
  • Diego Di Lorenzo
  • Silvana Archetti
  • Isabella Zanella
Article

Abstract

Mounting evidence indicates that the lysosome-autophagy pathway plays a critical role in iron release from ferritin, the main iron storage cellular protein, hence in the distribution of iron to the cells. The recent identification of nuclear receptor co-activator 4 as the receptor for ferritin delivery to selective autophagy sheds further light on the understanding of the mechanisms underlying this pathway. The emerging view is that iron release from ferritin through the lysosomes is a general mechanism in normal and tumour cells of different tissue origins, but it has not yet been investigated in brain cells. Defects in the lysosome-autophagy pathway are often involved in the pathogenesis of neurodegenerative disorders, and brain iron homeostasis disruption is a hallmark of many of these diseases. However, in most cases, it has not been established whether iron dysregulation is directly involved in the pathogenesis of the diseases or if it is a secondary effect derived from other pathogenic mechanisms. The recent evidence of the crucial involvement of autophagy in cellular iron handling offers new perspectives about the role of iron in neurodegeneration, suggesting that autophagy dysregulation could cause iron dyshomeostasis. In this review, we recapitulate our current knowledge on the routes through which iron is released from ferritin, focusing on the most recent advances. We summarise the current evidence concerning lysosome-autophagy pathway dysfunctions and those of iron metabolism and discuss their potential interconnections in several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases; amyotrophic lateral sclerosis; and frontotemporal lobar dementia.

Keywords

Ferritinophagy Nuclear receptor co-activator 4 NCOA4 Iron Autophagy Lysosome Neurodegeneration 

Abbreviations

AD

Alzheimer’s disease

ALAS2

5′-Aminolevulinate synthase 2

ALS

Amyotrophic lateral sclerosis

ALS2

Amyotrophic lateral sclerosis 2, juvenile

APs

Amyloid plaques

APP

Amyloid precursor protein (amyloid beta A4 precursor protein)

ATG5

Autophagy related 5

ATG7

Autophagy related 7

ATG9A

Autophagy related 9A

ATG11

Autophagy related 11

ATP13A2/PARK9

ATPase type 13A2

ATXN2

Ataxin 2

AV

Autophagic vacuole

BBB

Blood-brain barrier

C9orf72

Chromosome 9 open reading frame 72

C19orf12

Chromosome 19 open reading frame 12

CBD

Corticobasal degeneration

CHMP2B

Charged multivesicular body protein 2B

CMA

Chaperone-mediated autophagy

CoASY

Coenzyme-A synthase

CP

Ceruloplasmin

CTSC

Cathepsin C

DAO

d-Aminoacid oxidase

DCYTB

Duodenal cytochrome b (CYBRD1, cytochrome b reductase 1)

DMT1

Divalent metal transporter 1 (SLC11A2, solute carrier family 11, proton-coupled divalent metal ion transporter, member 2)

DJ-1/PARK7

Parkinson protein 7

FA2H

Fatty acid 2 hydroxylase

FBXL5

F-box and leucine-rich repeat protein 5

FPN1

Ferroportin 1 (SLC40A1, solute carrier family 40, iron-regulated transporter, member 1)

FT

Ferritin

FTH1

Ferritin heavy polypeptide 1

FTL

Ferritin light polypeptide

FTLD

Frontotemporal lobar dementia

FTMT

Mitochondrial ferritin

FRDA

Friedreich’s ataxia

FUS

Fused in sarcoma (FUS RNA-binding protein)

FXN

Frataxin

GABARAP

GABA(A) receptor-associated protein

GABARAPL1

GABA(A) receptor-associated protein-like 1

GABARAPL2

GABA(A) receptor-associated protein-like 2

GBA1

Glucocerebrosidase A1 (GBA, glucosidase beta, acid)

HAMP

Hepcidin

HCP1

Heme carrier protein 1 (SLC46A1, solute carrier family 46, folate transporter, member 1)

HD

Huntington’s disease

HEPH

Hephaestin

HF

Hereditary ferritinopathy

HFE

Haemochromatosis

HO1

Heme oxygenase 1 (HMOX1)

HTRA2/PARK13

HtrA serine peptidase 2

HTT

Huntingtin

IRE

Iron-responsive element

IRP1

Iron regulatory protein 1 (ACO1, aconitase 1)

IRP2

Iron regulatory protein 2 (IREB2, iron-responsive element-binding protein 2)

LAMP1

Lysosomal-associated membrane protein 1

LAMP2

Lysosomal-associated membrane protein 2

LC3

Microtubule-associated protein 1 light chain 3 alpha (MAP1LC3A)

LIP

Labile iron pool

LRRK2/PARK8

Leucine-rich repeat kinase 2

LSD

Lysosomal storage disease

MAPT

Microtubule-associated protein tau

MCOLN1

Mucolipin 1

MEF

Mouse embryonic fibroblast

MFN1

Mitoferrin 1 (SLC25A37, solute carrier family 25 member 37)

MFN2

Mitoferrin 2 (SLC25A28, solute carrier family 25 member 28)

MSA

Multiple system atrophy

mtor

Mechanistic target of rapamycin

NBIA

Neurodegeneration with brain iron accumulation

NBR1

Neighbour of BRCA1 gene 1

NCOA4

Nuclear receptor co-activator 4

NDP52

Nuclear dot protein 52 (CALCOCO2, calcium binding and coiled-coil domain 2)

NFT

Neurofibrillary tangles

NTBI

Non-transferrin bound iron

OPTN

Optineurin

PANK2

Pantothenate kinase 2

PARK2

Parkin

PCBP1

Poly rC-binding protein 1

PCBP2

Poly rC-binding protein 2

PD

Parkinson’s disease

PFN1

Profilin 1

PGRN

Progranulin (GRN, granulin)

PINK1/PARK6

PTEN-induced putative kinase 1

PLA2G6/PARK14

Phospholipase A2 group VI

PSEN1

Presenilin 1

PSENEN

Presenilin enhancer γ-secretase subunit

PSP

Progressive supranuclear palsy

RAB29/PARK16

RAB29 member RAS oncogene family (PARK16, Parkinson disease 16)

RAB38

RAB38 member RAS oncogene family

ROS

Reactive oxygen species

SG

Stress granule

SIGMAR1

Sigma non-opioid intracellular receptor 1

SILAC

Stable isotope labelling by amino acids in cell culture

SNCA

α-Synuclein

SNCA/PARK1

α-Synuclein gene mutation

SNCA/PARK4

α-Synuclein gene multiplication

SOD1

Superoxide dismutase 1

SOD2

Superoxide dismutase 2, mitochondrial

SQSTM1

Sequestosome 1

SREBF1

Sterol regulatory element-binding transcription factor 1

STEAP3

STEAP family member 3, metalloreductase

TDP-43

TAR DNA-binding protein (TARDBP)

TF

Transferrin

TFEB

Transcription factor EB

TFR1

Transferrin receptor 1 (TFRC, transferrin receptor)

TIM2

T cell immunoglobulin and mucin domain-2 (Timd2)

TMEM106B

Transmembrane protein 106B

TMPRSS6

Transmembrane protease, serine 6

UB

Ubiquitin

UBQLN2

Ubiquilin 2

UCH-L1/PARK5

Ubiquitin carboxyl-terminal esterase L1

UPS

Ubiquitin proteasome system

UTR

Untranslated region

VAPB

VAMP-associated protein B and C

VCP

Valosin-containing protein

VPS35/PARK17

Vacuolar protein sorting 35 (VPS35 retromer complex component)

WDR45

WD repeat domain 45

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  2. 2.Biotechnology Laboratory, Department of DiagnosticsCivic Hospital of BresciaBresciaItaly

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