Identification of Autophagy as a Functional Target Suitable for the Pharmacological Treatment of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) In Vitro

Enrica Zanuttigh, Kevork Derderian, Miriam A. Güra, Arie Geerlof, Ivano Di Meo, Chiara Cavestro, Stefan Hempfling, Stephanie Ortiz-Collazos, Mario Mauthe, Tomasz Kmieć, Eugenia Cammarota, Maria Carla Panzeri, Thomas Klopstock, Michael Sattler, Juliane Winkelmann, Ana C. Messias, Arcangela Iuso

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN.

Original languageEnglish
Article number267
JournalPharmaceutics
Volume15
Issue number1
DOIs
StatePublished - Jan 2023

Keywords

  • ABT-737
  • C19orf12
  • LC3
  • LY294002
  • autophagy
  • carbamazepine
  • mitochondria membrane protein-associated neurodegeneration (MPAN)
  • neurodegeneration with brain iron accumulation (NBIA)
  • oridonin
  • paroxetine

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