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Zanuttigh, E. ; Derderian, K. ; Güra, M. ; Geerlof, A. ; Di Meo, I.* ; Cavestro, C.* ; Hempfling, S. ; Ortiz Collazos, S. ; Mauthe, M.* ; Kmiec, T.* ; Cammarota, E.* ; Panzeri, M.C.* ; Klopstock, T.* ; Sattler, M. ; Winkelmann, J. ; Messias, A.C. ; Iuso, A.

Identification of autophagy as a functional target suitable for the pharmacological treatment of mitochondrial membrane protein-associated neurodegeneration (MPAN) in vitro.

Pharmaceutics 15:19 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Abt-737 ; C19orf12 ; Lc3 ; Ly294002 ; Autophagy ; Carbamazepine ; Mitochondria Membrane Protein-associated Neurodegeneration (mpan) ; Neurodegeneration With Brain Iron Accumulation (nbia) ; Oridonin ; Paroxetine; Patient
ISSN (print) / ISBN 1999-4923
e-ISSN 1999-4923
Zeitschrift Pharmaceutics
Quellenangaben Band: 15, Heft: 1, Seiten: , Artikelnummer: 19 Supplement: ,
Verlag MDPI
Verlagsort St Alban-anlage 66, Ch-4052 Basel, Switzerland
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Institute of Structural Biology (STB)
Förderungen NBIA Disorders Association
NBIA Poland
Euro-BioImaging Italian Fund
Hoffnungsbaum e.V.
NBIA Suisse
Million Dollar Bike Ride program