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

Filograna R, Lee S, Tiklová K, Mennuni M, Jonsson V, Ringnér M, Gillberg L, Sopova E, Shupliakov O, Koolmeister C, Olson L, Perlmann T, Larsson NG

PLoS Genet. 17 (9) e1009822 [2021-09-00; online 2021-09-27]

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.

Bioinformatics Long-term Support WABI [Collaborative]

Bioinformatics Support, Infrastructure and Training [Collaborative]

PubMed 34570766

DOI 10.1371/journal.pgen.1009822

Crossref 10.1371/journal.pgen.1009822

pmc: PMC8496783
pii: PGENETICS-D-21-00764