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

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009822
Author(s):  
Roberta Filograna ◽  
Seungmin Lee ◽  
Katarína Tiklová ◽  
Mara Mennuni ◽  
Viktor Jonsson ◽  
...  

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.

2016 ◽  
Vol 7 (4) ◽  
pp. 664-677 ◽  
Author(s):  
Sun Young Chung ◽  
Sarah Kishinevsky ◽  
Joseph R. Mazzulli ◽  
John Graziotto ◽  
Ana Mrejeru ◽  
...  

2012 ◽  
Vol 21 (22) ◽  
pp. 4827-4835 ◽  
Author(s):  
Seungmin Lee ◽  
Fredrik H. Sterky ◽  
Arnaud Mourier ◽  
Mügen Terzioglu ◽  
Staffan Cullheim ◽  
...  

2021 ◽  
pp. 1-24
Author(s):  
Juho-Matti Renko ◽  
Arun Kumar Mahato ◽  
Tanel Visnapuu ◽  
Konsta Valkonen ◽  
Mati Karelson ◽  
...  

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.


2021 ◽  
Vol 202 ◽  
pp. 173104
Author(s):  
Hui Shen ◽  
Kai Chen ◽  
Rosa Anna M. Marino ◽  
Ross A. McDevitt ◽  
Zheng-Xiong Xi

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