Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

Federico Miozzo, Eva P. Valencia-Alarcón, Luca Stickley, Michaëla Majcin Dorcikova, Francesco Petrelli, Damla Tas, Nicolas Loncle, Irina Nikonenko, Peter Bou Dib and Emi Nagoshi ()
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Federico Miozzo: University of Geneva
Eva P. Valencia-Alarcón: University of Geneva
Luca Stickley: University of Geneva
Michaëla Majcin Dorcikova: University of Geneva
Francesco Petrelli: University of Geneva
Damla Tas: University of Geneva
Nicolas Loncle: University of Geneva
Irina Nikonenko: University of Geneva
Peter Bou Dib: University of Bern
Emi Nagoshi: University of Geneva

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Progressive degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinson’s disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons causes mitochondrial abnormalities and locomotor impairments in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modeling and treating PD.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29075-0

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DOI: 10.1038/s41467-022-29075-0

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