{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T01:52:03Z","timestamp":1783734723299,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NBIA Suisse, Hoffnungsbaum e.V., and Euro-BioImaging Italian Fund","award":["MDBR-21-123-BPAN"],"award-info":[{"award-number":["MDBR-21-123-BPAN"]}]},{"name":"NBIA Poland and NBIA Disorders Association","award":["MDBR-21-123-BPAN"],"award-info":[{"award-number":["MDBR-21-123-BPAN"]}]},{"name":"Million Dollar Bike Ride program","award":["MDBR-21-123-BPAN"],"award-info":[{"award-number":["MDBR-21-123-BPAN"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/pharmaceutics15010267","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T05:45:33Z","timestamp":1673502333000},"page":"267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Identification of Autophagy as a Functional Target Suitable for the Pharmacological Treatment of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) In Vitro"],"prefix":"10.3390","volume":"15","author":[{"given":"Enrica","family":"Zanuttigh","sequence":"first","affiliation":[{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevork","family":"Derderian","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2485-2294","authenticated-orcid":false,"given":"Miriam A.","family":"G\u00fcra","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7295-9948","authenticated-orcid":false,"given":"Arie","family":"Geerlof","sequence":"additional","affiliation":[{"name":"Protein Expression and Purification Facility, Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4616-5623","authenticated-orcid":false,"given":"Ivano","family":"Di Meo","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6157-2403","authenticated-orcid":false,"given":"Chiara","family":"Cavestro","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4759-0186","authenticated-orcid":false,"given":"Stefan","family":"Hempfling","sequence":"additional","affiliation":[{"name":"Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"},{"name":"Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, 85747 Garching, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4125-9978","authenticated-orcid":false,"given":"Stephanie","family":"Ortiz-Collazos","sequence":"additional","affiliation":[{"name":"Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"},{"name":"Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, 85747 Garching, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0049-7961","authenticated-orcid":false,"given":"Mario","family":"Mauthe","sequence":"additional","affiliation":[{"name":"Molecular Cell Biology Section, Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"},{"name":"Expertise Center Movement Disorders Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Kmie\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurology and Epileptology, The Children\u2019s Memorial Health Institute, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Cammarota","sequence":"additional","affiliation":[{"name":"Alembic, Experimental Imaging Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carla","family":"Panzeri","sequence":"additional","affiliation":[{"name":"Alembic, Experimental Imaging Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[{"name":"Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University (LMU), 80336 Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sattler","sequence":"additional","affiliation":[{"name":"Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"},{"name":"Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, 85747 Garching, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Winkelmann","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"},{"name":"Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5449-9922","authenticated-orcid":false,"given":"Ana C.","family":"Messias","sequence":"additional","affiliation":[{"name":"Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"},{"name":"Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, 85747 Garching, 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