Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response
Artikel i vetenskaplig tidskrift, 2021
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.
Författare
Roberta Filograna
Karolinska Institutet
Seungmin Lee
Karolinska Institutet
Katarína Tiklová
Karolinska Institutet
Mara Mennuni
Karolinska Institutet
Viktor Jonsson
Chalmers, Biologi och bioteknik, Systembiologi
Markus Ringnér
Lunds universitet
Linda Gillberg
Karolinska Institutet
Elena Sopova
Saint Petersburg State University - Spsu
Karolinska Institutet
Oleg Shupliakov
Karolinska Institutet
Saint Petersburg State University - Spsu
Camilla Koolmeister
Karolinska Institutet
L Olson
Karolinska Institutet
Thomas Perlmann
Karolinska Institutet
Nils-Göran Larsson
Karolinska Institutet
PLoS Genetics
1553-7390 (ISSN) 1553-7404 (eISSN)
Vol. 17 9 e1009822Ämneskategorier
Neurovetenskaper
Cell- och molekylärbiologi
Immunologi inom det medicinska området
DOI
10.1371/journal.pgen.1009822
PubMed
34570766