Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain....

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Autores principales:	Roberta Filograna, Seungmin Lee, Katarína Tiklová, Mara Mennuni, Viktor Jonsson, Markus Ringnér, Linda Gillberg, Elena Sopova, Oleg Shupliakov, Camilla Koolmeister, Lars Olson, Thomas Perlmann, Nils-Göran Larsson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/61f2fcf7bb484163bdda169112e41b0e
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spelling	oai:doaj.org-article:61f2fcf7bb484163bdda169112e41b0e2021-12-02T20:03:18ZMitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.1553-73901553-740410.1371/journal.pgen.1009822https://doaj.org/article/61f2fcf7bb484163bdda169112e41b0e2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009822https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.Roberta FilogranaSeungmin LeeKatarína TiklováMara MennuniViktor JonssonMarkus RingnérLinda GillbergElena SopovaOleg ShupliakovCamilla KoolmeisterLars OlsonThomas PerlmannNils-Göran LarssonPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009822 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Roberta Filograna Seungmin Lee Katarína Tiklová Mara Mennuni Viktor Jonsson Markus Ringnér Linda Gillberg Elena Sopova Oleg Shupliakov Camilla Koolmeister Lars Olson Thomas Perlmann Nils-Göran Larsson Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
description	Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.
format	article
author	Roberta Filograna Seungmin Lee Katarína Tiklová Mara Mennuni Viktor Jonsson Markus Ringnér Linda Gillberg Elena Sopova Oleg Shupliakov Camilla Koolmeister Lars Olson Thomas Perlmann Nils-Göran Larsson
author_facet	Roberta Filograna Seungmin Lee Katarína Tiklová Mara Mennuni Viktor Jonsson Markus Ringnér Linda Gillberg Elena Sopova Oleg Shupliakov Camilla Koolmeister Lars Olson Thomas Perlmann Nils-Göran Larsson
author_sort	Roberta Filograna
title	Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
title_short	Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
title_full	Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
title_fullStr	Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
title_full_unstemmed	Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
title_sort	mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/61f2fcf7bb484163bdda169112e41b0e
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Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.

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