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Molecular Neurobiology

, Volume 56, Issue 4, pp 2466–2481 | Cite as

Impaired Mitophagy and Protein Acetylation Levels in Fibroblasts from Parkinson’s Disease Patients

  • Sokhna M. S. Yakhine-Diop
  • Mireia Niso-Santano
  • Mario Rodríguez-Arribas
  • Rubén Gómez-Sánchez
  • Guadalupe Martínez-Chacón
  • Elisabet Uribe-Carretero
  • José A. Navarro-García
  • Gema Ruiz-Hurtado
  • Ana Aiastui
  • J. Mark Cooper
  • Adolfo López de Munaín
  • José M. Bravo-San Pedro
  • Rosa A. González-PoloEmail author
  • José M. FuentesEmail author
Article

Abstract

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect.

Keywords

Acetylation Histone acetyltransferases Histone deacetylases LRRK2 Mitophagy 

Abbreviations

AA

anacardic acid

Ac-K

acetylated lysine

ATG

autophagy-related

BAF. A1

bafilomycin A1

CBP

CREB-binding protein

CCCP

carbonyl cyanide 3-chlorophenylhydrazone

COX IV

cytochrome c oxidase subunit 4

CsA

cyclosporin A

DiOC6(3)

3,3′-dihexyloxacarbocyanine iodide

DRP1

dynamin related protein 1

EBSS

Earle’s balanced salt solution

ERK1/2

extracellular signal-regulated kinase 1/2

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

GNAT

GCN5-related N-acetyltransferase

GFP

green fluorescent protein

H3

histone 3

H3K14

histone 3 lysine 14

H4

histone 4

H4K5K8K12

histone 4 lysine 5 lysine 8 lysine 12

H4K16

histone 4 lysine 16

HAT

histone acetyltransferase

HDAC

histone deacetylase

HFs

human fibroblasts

hMOF

human male absent of first

IPD

idiopathic Parkinson’s disease

JNK1

Jun-N-terminal kinase 1

LC3

light-chain microtubule-associated protein

LONP1

lon peptidase 1

LRRK2

leucine-rich repeat kinase 2

MAPK

mitogen-activated protein kinase

MMP

mitochondrial membrane potential

MPP+

1-methyl-4-phenylpyridinium iodide

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride

MTG

MitoTracker green

mTOR

mammalian target of rapamycin

NAD+

nicotinamide adenine dinucleotide

NAM

nicotinamide

PCAF

p300/CREB-binding protein-associated factor

PD

Parkinson’s disease

PI

propidium iodide

PINK1

PTEN-induced putative kinase 1

ROS

reactive oxygen species

RT

room temperature

SIRT

sirtuin

TIP60

tat-interactive protein 60

TMRM

tetramethylrhodamine methyl ester perchlorate

TSA

trichostatin A

WB

western blotting

WT

wild-type

Notes

Acknowledgments

We are grateful to the patients and donors without whom this work would not have been possible. The authors thank M. P. Delgado-Luceño and Dr. J.A. Tapia-Garcia. The authors also thank FUNDESALUD for helpful assistance.

Funding Information

SMS.Y-D was supported by Isabel Gemio Foundation. M. N-S was funded by “Ramon y Cajal Program (RYC-2016-20883) Spain. M. R-A. and E. U-C were supported by a FPU predoctoral fellowship (FPU13/01237 and FPU16/00684, respectively) from Ministerio de Educación, Cultura y Deporte, Spain. R. G-S. was supported by a Marie Sklodowska-Curie Individual Fellowship (IF-EF) (655027) from the European Commission. JM. B-S. P. was funded by La Ligue Contre le Cancer. JM. F. received research support from the Instituto de Salud Carlos III, CIBERNED (CB06/05/004) and Instituto de Salud Carlos III, FIS, (PI15/00034). RA. G-P. was supported by a “Contrato destinado a la retención y atracción del talento investigador, TA13009“ from Junta de Extremadura, and received a research support from the Instituto de Salud Carlos III, FIS, (PI14/00170). JM.C. was funded by a Parkinson’s UK project grant (G-1406). This work was also supported by “Fondo Europeo de Desarrollo Regional” (FEDER) from the European Union.

Supplementary material

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Figure S1

Determination of G2019S LRRK2 mutation and expression levels of SIRT2 and SIRT6. A/ Restriction enzyme of LRRK2 exon 41. Bfm I hydrolyses the exon 41 harboring the G2019S mutation into 2 bands (300 and 200 base pairs (bp)) confirming that the mutation is heterozygous. SIRT2 expression levels. B/ mRNA expression of SIRT2 by qPCR. Data are the normalized mean ± SD of three independent experiments. C-E/ Detection of two isoforms of SIRT2 by immunoblotting, SIRT2 isoform I (43 kDa) (C, D) and SIRT2 isoform II (39 kDa) (C, E). The densitometry of each isoform is normalized to GAPDH. The results correspond to the relative mean ± SD of three independent experiments, *p < 0.05 in comparison to Co, (Student’s t-test). F-H/ SIRT6 expression levels. F/ mRNA expression of SIRT6 by qPCR. Data are the normalized mean ± SD of three independent experiments, **p < 0.01 versus Co, (Student’s t-test). G, H/ Assessment of SIRT6 expression and its quantification to referenced GAPDH. Data are the normalized means ± SD of three independent experiments, **p < 0.01 up to Co, (Student’s t-test). (PNG 319 kb)

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Figure S2

Ac-K proteins and mRNA expression levels of the HAT family. A, B/ Immunofluorescence intensity of labeled nuclear Ac-K proteins (red) in HFs, the nuclei were stained with Hoechst 33,342 (blue). Original magnification: 40X, scale bar corresponds to 10 μm. B/ Represents the quantification of the fluorescence intensity (n = 60 cells/condition). Data are the mean ± SD of two independent experiments, **p < 0.01, ***p˂0.001 in comparison to Co, (Student’s t-test). p300 (C) and PCAF (D) are members of the p300/CBP and GNAT families, respectively. Members of the MYST family are hMOF (E) and TIP60 (F). Their mRNA expression levels were assessed by qPCR, and the results represent the relative mean ± SD of at least three independent experiments, *p˂0.05, **p˂0.01, ***p˂0.001 versus Co, (Student’s t-test). G/ Immunofluorescence intensity of labeled cytoplasmic Ac-K proteins (red) in HFs treated with TSA (1 μM) during 4 h. Scale bar corresponds to 10 μm. (PNG 340 kb)

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Figure S3

mRNA expression levels of class I and II HDACs. A-C/ Class I HDACs includes HDAC1 (A), HDAC2 (B) and HDAC3 (C). D, E/ Class II HDACs includes HDAC4 (D) and HDAC6 (E). Their mRNA expression levels were assessed by qPCR, and the results correspond to the relative mean ± SD of three independent experiments, *p˂0.05, **p˂0.01, ***p˂0.001 versus Co, (Student’s t-test). (PNG 104 kb)

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Figure S4

Cell viability with HDAC inhibitors. A, B/ HFs were treated with TSA (0–100 μM) or NAM (0–100 mM) for 24 h. Cell viability was assessed by the colorimetric test MTT. Data correspond to the normalized mean percentage of untreated cells, *p˂0.05, **p˂0.01, ***p˂0.001, (Student’s t-test). C, D/ Cells were treated with TSA (1 μM) or NAM (1 mM) for 4 h. Histone 3 acetylated on lysine 14 (Ac-H3K14) was detected by immunoblotting and was normalized to total Histone 3 (H3). E/ Cells were treated overnight with EX-527 (1 μM). Cells were stained with propidium iodide (PI), and the percentage of PI+ cells was evaluated by flow cytometry, (n = 10.000 events). Data are the mean percentage ± SD of three independent experiments, *p˂0.05, **p˂0.01, (Student’s t-test). (PNG 236 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sokhna M. S. Yakhine-Diop
    • 1
    • 2
  • Mireia Niso-Santano
    • 1
    • 2
  • Mario Rodríguez-Arribas
    • 1
    • 2
  • Rubén Gómez-Sánchez
    • 3
  • Guadalupe Martínez-Chacón
    • 1
    • 2
  • Elisabet Uribe-Carretero
    • 1
    • 2
  • José A. Navarro-García
    • 4
  • Gema Ruiz-Hurtado
    • 4
  • Ana Aiastui
    • 2
    • 5
    • 6
  • J. Mark Cooper
    • 7
  • Adolfo López de Munaín
    • 2
    • 6
    • 8
    • 9
    • 10
  • José M. Bravo-San Pedro
    • 11
    • 12
    • 13
    • 14
    • 15
  • Rosa A. González-Polo
    • 1
    • 2
    Email author
  • José M. Fuentes
    • 1
    • 2
    Email author
  1. 1.Departamento de Bioquímica y Biología Molecular y Genética. Facultad de Enfermería y Terapia OcupacionalUniversidad de ExtremaduraCáceresSpain
  2. 2.Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED) MadridMadridSpain
  3. 3.Department of Cell Biology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
  4. 4.Laboratorio de Hipertensión y Riesgo Cardiovascular and Unidad de Hipertensión, Instituto de Investigación imas12Hospital Universitario 12 de OctubreMadridSpain
  5. 5.Cell Culture PlatformDonostia University HospitalSan SebastiánSpain
  6. 6.Neuroscience Area of Biodonostia Health Research InstituteDonostia University HospitalSan SebastiánSpain
  7. 7.Department of Clinical and Movement Neurosciences, Institute of Neurology LondonUniversity College LondonLondonUK
  8. 8.Department of NeurologyDonostia University HospitalSan SebastiánSpain
  9. 9.Ilundain FundazioaSan SebastiánSpain
  10. 10.Department of NeurosciencesUniversity of the Basque Country UPV-EHUSan SebastiánSpain
  11. 11.Equipe 11 labellisée Ligue contre le CancerCentre de Recherche des CordeliersParisFrance
  12. 12.INSERM U1138ParisFrance
  13. 13.Université Paris Descartes/Paris V, Sorbonne Paris CitéParisFrance
  14. 14.Université Pierre et Marie Curie/Paris VIParisFrance
  15. 15.Gustave Roussy Comprehensive Cancer InstituteVillejuifFrance

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