Reference : Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biochemistry, biophysics & molecular biology
	To cite this reference:	http://hdl.handle.net/10993/51271

Title :	Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.
Language :	English
Author, co-author :	Wasner, Kobi [> >]
	Smajic, Semra [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
	Ghelfi, Jenny [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
	Delcambre, Sylvie [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
	Prada-Medina, Cesar A. [> >]
	Knappe, Evelyn [> >]
	Arena, Giuseppe [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
	Mulica, Patrycja [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
	Agyeah, Gideon [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
	Rakovic, Aleksandar [> >]
	Boussaad, Ibrahim [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
	Badanjak, Katja [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
	Ohnmacht, Jochen [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
	Gerardy, Jean-Jacques [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
	Takanashi, Masashi [> >]
	Trinh, Joanne [> >]
	Mittelbronn, Michel [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
	Hattori, Nobutaka [> >]
	Klein, Christine [> >]
	Antony, Paul [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
	Seibler, Philip [> >]
	Spielmann, Malte [> >]
	Pereira, Sandro L. [> >]
	Grünewald, Anne [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
Publication date :	2022
Journal title :	Movement disorders : official journal of the Movement Disorder Society
Peer reviewed :	Yes (verified by ORBilu)
ISSN :	0885-3185
e-ISSN :	1531-8257
Country :	United States
Keywords :	[en] Parkinson's disease ; induced pluripotent stem cells ; mitochondrial DNA ; parkin; neuroinflammation
Abstract :	[en] BACKGROUND: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons. OBJECTIVES: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level. METHODS: We generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron-microglia co-cultures. RESULTS: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron-microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS. CONCLUSIONS: Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Permalink :	http://hdl.handle.net/10993/51271
DOI :	10.1002/mds.29025
Commentary :	© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
FnR project :	FnR ; FNR9631103 > Anne Grünewald > Model IPD > Modelling Idiopathic Parkinson’s Disease-associated Somatic Variation In Dopaminergic Neurons > 01/01/2016 > 31/12/2022 > 2015

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