Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease

Kahori Shiba-Fukushima, Kei Ichi Ishikawa, Tsuyoshi Inoshita, Nana Izawa, Masashi Takanashi, Shigeto Sato, Osamu Onodera, Wado Akamatsu, Hideyuki Okano, Yuzuru Imai, Nobutaka Hattori

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls.We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon DWmreduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

Original languageEnglish
Article numberddx201
Pages (from-to)3172-3185
Number of pages14
JournalHuman Molecular Genetics
Volume26
Issue number16
DOIs
Publication statusPublished - 2017 Aug 15

Fingerprint

Ubiquitin
Parkinson Disease
Dopaminergic Neurons
Mitochondrial Degradation
Tyrosine 3-Monooxygenase
Mitochondria
Phosphorylation
Neurons
Induced Pluripotent Stem Cells
Mutation
Ubiquitin-Protein Ligases
Mitochondrial Membrane Potential
Diptera
Quality Control
Drosophila
Phosphotransferases
Brain
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Shiba-Fukushima, K., Ishikawa, K. I., Inoshita, T., Izawa, N., Takanashi, M., Sato, S., ... Hattori, N. (2017). Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease. Human Molecular Genetics, 26(16), 3172-3185. [ddx201]. https://doi.org/10.1093/hmg/ddx201

Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease. / Shiba-Fukushima, Kahori; Ishikawa, Kei Ichi; Inoshita, Tsuyoshi; Izawa, Nana; Takanashi, Masashi; Sato, Shigeto; Onodera, Osamu; Akamatsu, Wado; Okano, Hideyuki; Imai, Yuzuru; Hattori, Nobutaka.

In: Human Molecular Genetics, Vol. 26, No. 16, ddx201, 15.08.2017, p. 3172-3185.

Research output: Contribution to journalArticle

Shiba-Fukushima, K, Ishikawa, KI, Inoshita, T, Izawa, N, Takanashi, M, Sato, S, Onodera, O, Akamatsu, W, Okano, H, Imai, Y & Hattori, N 2017, 'Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease', Human Molecular Genetics, vol. 26, no. 16, ddx201, pp. 3172-3185. https://doi.org/10.1093/hmg/ddx201
Shiba-Fukushima K, Ishikawa KI, Inoshita T, Izawa N, Takanashi M, Sato S et al. Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease. Human Molecular Genetics. 2017 Aug 15;26(16):3172-3185. ddx201. https://doi.org/10.1093/hmg/ddx201
Shiba-Fukushima, Kahori ; Ishikawa, Kei Ichi ; Inoshita, Tsuyoshi ; Izawa, Nana ; Takanashi, Masashi ; Sato, Shigeto ; Onodera, Osamu ; Akamatsu, Wado ; Okano, Hideyuki ; Imai, Yuzuru ; Hattori, Nobutaka. / Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 16. pp. 3172-3185.
@article{f1e9d3a789d641e2bcdfc81c8ac79dd1,
title = "Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease",
abstract = "The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls.We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon DWmreduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.",
author = "Kahori Shiba-Fukushima and Ishikawa, {Kei Ichi} and Tsuyoshi Inoshita and Nana Izawa and Masashi Takanashi and Shigeto Sato and Osamu Onodera and Wado Akamatsu and Hideyuki Okano and Yuzuru Imai and Nobutaka Hattori",
year = "2017",
month = "8",
day = "15",
doi = "10.1093/hmg/ddx201",
language = "English",
volume = "26",
pages = "3172--3185",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "16",

}

TY - JOUR

T1 - Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease

AU - Shiba-Fukushima, Kahori

AU - Ishikawa, Kei Ichi

AU - Inoshita, Tsuyoshi

AU - Izawa, Nana

AU - Takanashi, Masashi

AU - Sato, Shigeto

AU - Onodera, Osamu

AU - Akamatsu, Wado

AU - Okano, Hideyuki

AU - Imai, Yuzuru

AU - Hattori, Nobutaka

PY - 2017/8/15

Y1 - 2017/8/15

N2 - The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls.We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon DWmreduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

AB - The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls.We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon DWmreduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

UR - http://www.scopus.com/inward/record.url?scp=85027715258&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027715258&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddx201

DO - 10.1093/hmg/ddx201

M3 - Article

C2 - 28541509

AN - SCOPUS:85027715258

VL - 26

SP - 3172

EP - 3185

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 16

M1 - ddx201

ER -