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Iron and Neurodegeneration: Is Ferritinophagy the Link?

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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.

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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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  1. Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy

    Giorgio Biasiotto & Isabella Zanella

  2. Biotechnology Laboratory, Department of Diagnostics, Civic Hospital of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy

    Giorgio Biasiotto, Diego Di Lorenzo, Silvana Archetti & Isabella Zanella

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Biasiotto, G., Di Lorenzo, D., Archetti, S. et al. Iron and Neurodegeneration: Is Ferritinophagy the Link?. Mol Neurobiol 53, 5542–5574 (2016). https://doi.org/10.1007/s12035-015-9473-y

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