Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response
(2021) In PLoS Genetics 17(9). p.1009822-1009822- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2021-10-07
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS Genetics
- volume
- 17
- issue
- 9
- pages
- 19 pages
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- scopus:85118097032
- pmid:34570766
- ISSN
- 1553-7404
- DOI
- 10.1371/journal.pgen.1009822
- language
- English
- LU publication?
- yes
- id
- 6da7f8f9-a582-45e3-a35f-616aae333302
- date added to LUP
- 2021-10-04 16:22:10
- date last changed
- 2024-06-15 17:25:47
@article{6da7f8f9-a582-45e3-a35f-616aae333302, abstract = {{<p>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.</p>}}, author = {{Filograna, Roberta and Lee, Seungmin and Tiklova, Katarina and Mennuni, Mara and Jonsson, Viktor and Ringnér, Markus and Gillberg, Linda and Sopova, Elena and Shupliakov, Oleg and Koolmeister, Camilla and Olson, Lars and Perlmann, Thomas and Larsson, Nils-Göran}}, issn = {{1553-7404}}, language = {{eng}}, month = {{10}}, number = {{9}}, pages = {{1009822--1009822}}, publisher = {{Public Library of Science (PLoS)}}, series = {{PLoS Genetics}}, title = {{Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response}}, url = {{http://dx.doi.org/10.1371/journal.pgen.1009822}}, doi = {{10.1371/journal.pgen.1009822}}, volume = {{17}}, year = {{2021}}, }