FYCO1 Increase and Effect of Arimoclomol–Treatment in Human <i>VCP</i>–Pathology
Anne-Katrin Guettsches,
Nancy Meyer,
René P. Zahedi,
Teresinha Evangelista,
Thomas Muentefering,
Tobias Ruck,
Emmanuelle Lacene,
Christoph Heute,
Humberto Gonczarowska-Jorge,
Benedikt Schoser,
Sabine Krause,
Andreas Hentschel,
Matthias Vorgerd,
Andreas Roos
Affiliations
Anne-Katrin Guettsches
Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany
Nancy Meyer
Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Duisburg–Essen, 45147 Essen, Germany
René P. Zahedi
Manitoba Centre for Proteomics and Systems Biology, 715 McDermot Aveue, Winnipeg, MB R3E 3P4, Canada
Teresinha Evangelista
Nord/Est/Ile–de–France Neuromuscular Reference Center, Unité de Morphologie Neuromusculaire, Institute of Myology, Pitié–Salpêtrière Hospital, APHP, Sorbonne University, 75013 Paris, France
Thomas Muentefering
Department of Neurology, Medical Faculty, Heinrich–Heine–University Düsseldorf, 40225 Düsseldorf, Germany
Tobias Ruck
Department of Neurology, Medical Faculty, Heinrich–Heine–University Düsseldorf, 40225 Düsseldorf, Germany
Emmanuelle Lacene
Nord/Est/Ile–de–France Neuromuscular Reference Center, Unité de Morphologie Neuromusculaire, Institute of Myology, Pitié–Salpêtrière Hospital, APHP, Sorbonne University, 75013 Paris, France
Christoph Heute
Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Duisburg–Essen, 45147 Essen, Germany
Humberto Gonczarowska-Jorge
Leibniz–Institut für Analytische Wissenschaften—ISAS—e.V, 44227 Dortmund, Germany
Benedikt Schoser
Department of Neurology, Friedrich–Baur–Institute, Ludwig–Maximilians–University Munich, Ziemssenstr. 1a, 80336 Munich, Germany
Sabine Krause
Department of Neurology, Friedrich–Baur–Institute, Ludwig–Maximilians–University Munich, Ziemssenstr. 1a, 80336 Munich, Germany
Andreas Hentschel
Leibniz–Institut für Analytische Wissenschaften—ISAS—e.V, 44227 Dortmund, Germany
Matthias Vorgerd
Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany
Andreas Roos
Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany
Dominant VCP–mutations cause a variety of neurological manifestations including inclusion body myopathy with early–onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin–dependent protein degradation. The latter function accords with the presence of protein aggregates in muscle biopsy specimens derived from VCP–patients. Studying the proteomic signature of VCP–mutant fibroblasts, we identified a (pathophysiological) increase of FYCO1, a protein involved in autophagosome transport. We confirmed this finding applying immunostaining also in muscle biopsies derived from VCP–patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in VCP–patient derived cells. This finding was accompanied by increased abundance of proteins involved in immune response with a direct impact on protein clearaqnce as well as by elevation of pro–survival proteins as unravelled by untargeted proteomic profiling. Hence, the combined results of our study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts.
