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

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.

The utility and caveat of split-GAL4s in the study of neurodegeneration

“…We and others have previously shown the loss of dopaminergic neurons (DA) within the protocerebral anterior medial (PAM) cluster by genetic or pharmacological insults in adult Drosophila brains [11,17–19]. Although the number of PAM neuron loss observed so far varies between 15% and 80%, other DA clusters remain unaffected.…”

“…Following fly strains were obtained from the Bloomington Drosophila stock center (BDSC): 20XUAS-6XGFP (Bl #52261), MB316B (Bl #68317), MB032B (Bl #68302), MB056B (Bl #68276), MB109B (Bl #68261), MB025B (Bl #68299). UAS-Lrrk I1915T was described previously [11,12].…”

“…Drosophila brains [11,[17][18][19]. Although the number of PAM neuron loss observed so far varies between 15% and 80%, other DA clusters remain unaffected.…”

“…Immunostaining was performed as previously described in [11]. Briefly, fly heads were fully dissected and fixed in 400mL of 4% paraformaldehyde (PFA), 0.3% Triton X-100 for 20 min on ice.…”

Chiral MoSe2 Nanoparticles for Ultrasensitive Monitoring of Reactive Oxygen Species In Vivo

“…Moreover, excessive production of ROS is associated with certain neurodegenerative diseases, such as Parkinson's disease (PD). [41,42] It can be seen that the nanoprobe showed no significant cytotoxicity to BV2 microglial cell (BV2 cell) line at the concentration below 300 µg mL −1 (Figure S10A,B, Supporting Information). The data also displayed that the value of the ΔCD signal is linearly related to the content of H 2 O 2 in BV2 cells (Figure S17, Supporting Information), indicating that this nanoprobe could be used in the detection of ROS as a clinical diagnosis method for neurodegenerative diseases.…”