%0 Journal Article
%T FYCO1 Increase and Effect of Arimoclomol-Treatment in Human VCP-Pathology.
%A Guettsches AK
%A Meyer N
%A Zahedi RP
%A Evangelista T
%A Muentefering T
%A Ruck T
%A Lacene E
%A Heute C
%A Gonczarowska-Jorge H
%A Schoser B
%A Krause S
%A Hentschel A
%A Vorgerd M
%A Roos A
%J Biomedicines
%V 10
%N 10
%D Sep 2022 30
%M 36289705
%F 4.757
%R 10.3390/biomedicines10102443
%X 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.