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

['Roberta Filograna', 'Department Of Medical Biochemistry', 'Biophysics', 'Karolinska Institutet', 'Stockholm', 'Seungmin Lee', 'Katarína Tiklová', 'Department Of Cell', 'Molecular Biology', 'Mara Mennuni']

Date: 2021-11

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.

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopamine (DA)-producing neurons and strongly compromised motor performance. Multiple observations suggest that DA neurons are particularly prone to acquire mitochondrial damage in adult life. This acquired mitochondrial dysfunction likely impairs DA neuron function and contributes to cell death. To study the consequences of adult-onset mitochondrial dysfunction in DA neurons, we generated a conditional activatable knockout mouse model lacking Mitofusin 2, a key regulator of mitochondrial homeostasis. This animal model allows the induction of mitochondrial dysfunction selectively in adult DA neurons and leads to motor defects and the typical pattern of neurodegeneration seen in PD. By studying gene expression in isolated DA neurons at early disease stages and by using in situ approaches on brain sections, we report an early onset of an inflammatory response. Inflammation is present already when the mutant DA neurons display the first signs of mitochondrial fragmentation and precedes the onset of respiratory chain dysfunction and neurodegeneration. The inflammatory response in DA neurons and activation of surrounding glia thus likely exacerbates or drives the neurodegenerative process in this animal model of adult-onset PD.

Funding: This study was supported by grants to NGL from Vetenskapsrådet https://www.vr.se (2015-00418), Knut och Alice Wallenbergs Stiftelse https://kaw.wallenberg.org , the European Research Council https://erc.europa.eu (Advanced Grant 2016-741366), Cancerfonden https://www.cancerfonden.se (2018.602), Hjärnfonden https://www.hjarnfonden.se . TP was supported by grants from Knut och Alice Wallenbergs Stiftelse https://kaw.wallenberg.org , Vetenskapsrådet https://www.vr.se (2016-02506) and Torsten Söderbergs Stiftelse https://www.torstensoderbergsstiftelse.se . In addition, MR and VJ were financially supported by the Knut och Alice Wallenbergs Stiftelse https://kaw.wallenberg.org as part of the National Bioinformatics Infrastructure Sweden at SciLifeLab. OS was supported by grants from Vetenskapsrådet https://www.vr.se (2020-01731) and Hjärnfonden https://www.hjarnfonden.se . OS and ES were also supported by the RSF https://rscf.ru/en/ (21-15-00227). LO was supported by Vetenskapsrådet https://www.vr.se and Hjärnfonden https://www.hjarnfonden.se . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2021 Filograna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Over the last decades, the role of mitochondrial dysfunction in the pathophysiology of PD has been much debated (reviewed in [ 12 ]). Although mitochondrial impairment is heavily implicated in both idiopathic and familial forms of PD, the precise contribution of these organelles to neurodegeneration remains unclear. There is experimental evidence that mitochondria are required to maintain specific cellular functions in DA neurons, such as anterograde axonal transport [ 13 ] and DA release by nerve terminals in the striatum [ 14 ]. In fact, mouse models with deletions [ 15 ] or depletion of mtDNA [ 16 ] selectively in midbrain DA neurons mirror the motor phenotypes and the typical neurodegeneration present in PD patients. One weakness with these sets of experiments is that the mitochondrial defects are induced in neurons already during the embryonic stage, which argue that the observed Parkinson-like phenotypes can be the result of both neurodevelopmental and neurodegenerative processes. To study the effects of adult-onset mitochondrial damage in PD, we disrupted the Mitofusin 2 (Mfn2) gene in midbrain DA neurons of adult mice. The Mfn2 gene encodes a key component of mitochondrial fusion machinery and is therefore a major player in several mitochondrial pathways, e.g. trafficking, turnover, contacts with other organelles and organelle homeostasis (reviewed in [ 17 , 18 ]). In mice, the tissue-specific ablation of Mfn2 in different neuronal circuits causes abnormalities in mitochondrial morphology and severe neurological defects [ 19 , 20 ]. Here, we identify a detailed timeline of molecular events driving the severe and progressive parkinsonism in mice with disruption of Mfn2 in the adult nigrostriatal DA system. By using transcriptomic analyses of isolated adult midbrain DA neurons, we show that loss of mitochondrial homeostasis triggers an early-onset immune response, that precedes DA neuron death and therefore likely drives or exacerbates the degenerative process.

Most neuronal cells have a life span similar to that of the whole organism and are rarely or never replaced [ 1 ]. As a consequence, neurons are prone to accumulate defects which affect their function and plasticity, and even compromise their long-term survival. The cortical surface of the cerebellum and certain brain nuclei, e.g. Substantia nigra pars compacta (SNpc), are particularly vulnerable to acquired damage [ 2 , 3 ], whereas other regions, e.g. hippocampus, putamen, and hypothalamus almost completely preserve their neuronal integrity during adult life [ 4 ]. The loss of dopamine (DA) neurons in SNpc occurs at an estimated rate of ~5–10% per decade [ 5 , 6 ]. Notably, a massive degeneration of this neuronal population accounts for the motor symptoms found in Parkinson’s disease (PD) patients. The selective vulnerability of DA neurons seems to be caused by their intrinsic biochemical and physiological properties. DA neurons in SNpc have rhythmic electrical (pacemaker) activity and experience increased oxidative stress, presumably due to the high dopamine synthesis rate [ 7 ]. The SN is also highly enriched in microglia cells [ 8 ], which, if activated, may generate a potentially detrimental pro-inflammatory environment. In addition, DA neurons are thought to be particularly sensitive to mitochondrial damage, which is mainly acquired during the lifespan of the neuron rather than inherited. In fact, somatic deletions in the mitochondrial DNA (mtDNA) accumulate in DA neurons in SN of aged humans [ 9 ] and PD patients [ 10 , 11 ] and lead to a mosaic pattern of respiratory chain deficiency.

Results and discussion

[END]

[1] Url: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009822

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